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1
Lasrado, Ninaad, Rajkumar Arumugam, Mahima T. Rasquinha, Meghna Sur, David Steffen, and Jay Reddy. "Mt10-CVB3 Vaccine Virus Protects against CVB4 Infection by Inducing Cross-Reactive, Antigen-Specific Immune Responses." Microorganisms 9, no. 11 (November 10, 2021): 2323. http://dx.doi.org/10.3390/microorganisms9112323.
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Group B coxsackieviruses (CVB) containing six serotypes, B1–B6, affect various organs, and multiple serotypes can induce similar diseases such as myocarditis and pancreatitis. Yet, no vaccines are currently available to prevent these infections. Translationally, the derivation of vaccines that offer protection against multiple serotypes is highly desired. In that direction, we recently reported the generation of an attenuated strain of CVB3, termed Mt10, which completely protects against both myocarditis and pancreatitis induced by the homologous wild-type CVB3 strain. Here, we report that the Mt10 vaccine can induce cross-protection against multiple CVB serotypes as demonstrated with CVB4. We note that the Mt10 vaccine could induce cross-reactive neutralizing antibodies (nABs) against both CVB1 and CVB4. In challenge studies with CVB4, the efficacy of the Mt10 vaccine was found to be 92%, as determined by histological evaluation of the heart and pancreas. Antibody responses induced in Mt10/CVB4 challenged animals indicated the persistence of cross-reactive nABs against CVB1, CVB3, and CVB4. Evaluation of antigen-specific immune responses revealed viral protein 1 (VP1)-reactive antibodies, predominantly IgG2a, IgG2b, IgG3, and IgG1. Similarly, by using major histocompatibility complex class II tetramers, we noted induction of VP1-specific CD4 T cells capable of producing multiple T cell cytokines, with interferon-γ being predominant. Finally, none of the vaccine recipients challenged with CVB4 revealed the presence of viral nucleic acid in the heart or pancreas. Taken together, our data suggest that the Mt10 vaccine can prevent infections caused by multiple CVB serotypes, paving the way for the development of monovalent CVB vaccines to prevent heart and pancreatic diseases of enteroviral origin.
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Mone, Kiruthiga, Ninaad Lasrado, Meghna Sur, and Jay Reddy. "Vaccines against Group B Coxsackieviruses and Their Importance." Vaccines 11, no. 2 (January 27, 2023): 274. http://dx.doi.org/10.3390/vaccines11020274.
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The group B coxsackieviruses (CVBs) exist in six serotypes (CVB1 to CVB6). Disease associations have been reported for most serotypes, and multiple serotypes can cause similar diseases. For example, CVB1, CVB3, and CVB5 are generally implicated in the causation of myocarditis, whereas CVB1 and CVB4 could accelerate the development of type 1 diabetes (T1D). Yet, no vaccines against these viruses are currently available. In this review, we have analyzed the attributes of experimentally tested vaccines and discussed their merits and demerits or limitations, as well as their impact in preventing infections, most importantly myocarditis and T1D.
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Gangaplara, Arunakumar, Chandirasegaran Massilamany, Ninaad Lasrado, David Steffen, and Jay Reddy. "Evidence for Anti-Viral Effects of Complete Freund’s Adjuvant in the Mouse Model of Enterovirus Infection." Vaccines 8, no. 3 (July 7, 2020): 364. http://dx.doi.org/10.3390/vaccines8030364.
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Group B coxsackieviruses (CVBs) belonging to the genus, Enterovirus and contain six serotypes that induce various diseases, whose occurrence may involve the mediation of more than one serotype. We recently identified immunogenic epitopes within coxsackieviruses B3 (CVB3) viral protein 1 that induce anti-viral T cell responses in mouse models of CVB infections. In our investigations to determine the protective responses of the viral epitopes, we unexpectedly noted that animals immunized with complete Freund’s adjuvant (CFA) alone and later challenged with CVB3 were completely protected against myocarditis. Similarly, the pancreatitis-inducing ability of CVB3 was remarkably reduced to only 10% in the CFA group as opposed to 73.3% in the control group that received no CFA. Additionally, no mortalities were noted in the CFA group, whereas 40% of control animals died during the course of 21 days post-infection with CVB3. Taken together, our data suggest that the adjuvant effects of CFA may be sufficient for protection against CVB infections. These observations may provide new insights into our understanding of the occurrence of viral infections.
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Fu, Yuxuan, and Sidong Xiong. "Exosomes mediate Coxsackievirus B3 transmission and expand the viral tropism." PLOS Pathogens 19, no. 1 (January 12, 2023): e1011090. http://dx.doi.org/10.1371/journal.ppat.1011090.
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Specific virus-receptor interactions are important determinants in viral host range, tropism and pathogenesis, influencing the location and initiation of primary infection as well as viral spread to other target organs/tissues in the postviremic phase. Coxsackieviruses of Group B (CVB) and its six serotypes (CVB1-6) specifically interact with two receptor proteins, coxsackievirus-adenovirus receptor (CAR) and decay-accelerating factor (DAF), and cause various lesions in most permissive tissues. However, our previous data and other studies revealed that virus receptor-negative cells or tissues can be infected with CVB type 3 (CVB3), which can also effectively replicate. To study this interesting finding, we explored the possibility that exosomes are involved in CVB3 tropism and that exosomes functionally enhance CVB3 transmission. We found that exosomes carried and delivered CVB3 virions, resulting in efficient infection in receptor-negative host cells. We also found that delivery of CVB3 virions attached to exosomes depended on the virus receptor CAR. Importantly, exosomes carrying CVB3 virions exhibited greater infection efficiency than free virions because they accessed various entry routes, overcoming restrictions to viral tropism. In vivo experiments demonstrated that inhibition of exosome coupling with virions attenuated CVB3-induced immunological system dysfunction and reduced mortality. Our study describes a new mechanism in which exosomes contribute to viral tropism, spread, and pathogenesis.
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Girn, Jaskamal, Mojgan Kavoosi, and Janet Chantler. "Enhancement of coxsackievirus B3 infection by antibody to a different coxsackievirus strain." Journal of General Virology 83, no. 2 (February 1, 2002): 351–58. http://dx.doi.org/10.1099/0022-1317-83-2-351.
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Group B coxsackieviruses (CVBs) are a major cause of viral myocarditis and pancreatitis in humans and produce a similar pattern of disease in inbred strains of mice. As there are six strains of CVBs, individuals can be infected with multiple serotypes. This raises the possibility of antibody enhancement of infectivity (AEI) by cross-reactive but non-neutralizing antibody to a different strain from a prior infection. To determine whether AEI plays a role in coxsackievirus pathogenesis, an in vitro system using the murine macrophage cell line J774.1 was tested for enhanced infection when incubated with CVB3 plus anti-CVB2 antibody. Yields of virus were found to increase by 10–50-fold and the percentage of infected cells increased proportionately. The effect was Fc-mediated as F(ab′)2 fragments of the antibody could not mediate the effect. To determine whether AEI could also be demonstrated in vivo CVB3 was injected into 5-week-old mice together with mouse polyclonal anti-CVB2. Controls included mice injected with PBS or CVB3 alone. Results showed that the titres of virus in tissues of animals injected with virus plus antibody were 1–2 logs higher than when virus was injected alone. This was accompanied by greater histopathological damage, particularly in the heart. These results have implications for human disease as infection with multiple strains likely occurs during the lifetime of an individual.
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Tracy, S., K. M. Drescher, N. M. Chapman, K. S. Kim, S. D. Carson, S. Pirruccello, P. H. Lane, J. R. Romero, and J. S. Leser. "Toward Testing the Hypothesis that Group B Coxsackieviruses (CVB) Trigger Insulin-Dependent Diabetes: Inoculating Nonobese Diabetic Mice with CVB Markedly Lowers Diabetes Incidence." Journal of Virology 76, no. 23 (December 1, 2002): 12097–111. http://dx.doi.org/10.1128/jvi.76.23.12097-12111.2002.
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ABSTRACT Insulin-dependent (type 1) diabetes mellitus (T1D) onset is mediated by individual human genetics as well as undefined environmental influences such as viral infections. The group B coxsackieviruses (CVB) are commonly named as putative T1D-inducing agents. We studied CVB replication in nonobese diabetic (NOD) mice to assess how infection by diverse CVB strains affected T1D incidence in a model of human T1D. Inoculation of 4- or 8-week-old NOD mice with any of nine different CVB strains significantly reduced the incidence of T1D by 2- to 10-fold over a 10-month period relative to T1D incidences in mock-infected control mice. Greater protection was conferred by more-pathogenic CVB strains relative to less-virulent or avirulent strains. Two CVB3 strains were employed to further explore the relationship of CVB virulence phenotypes to T1D onset and incidence: a pathogenic strain (CVB3/M) and a nonvirulent strain (CVB3/GA). CVB3/M replicated to four- to fivefold-higher titers than CVB3/GA in the pancreas and induced widespread pancreatitis, whereas CVB3/GA induced no pancreatitis. Apoptotic nuclei were detected by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay in CVB3/M-infected pancreata but not in CVB3/GA-infected pancreata. In situ hybridization detected CVB3 RNA in acinar tissue but not in pancreatic islets. Although islets demonstrated inflammatory infiltrates in CVB3-protected mice, insulin remained detectable by immunohistochemistry in these islets but not in those from diabetic mice. Enzyme-linked immunosorbent assay-based examination of murine sera for immunoglobulin G1 (IgG1) and IgG2a immunoreactivity against diabetic autoantigens insulin and HSP60 revealed no statistically significant relationship between CVB3-protected mice or diabetic mice and specific autoimmunity. However, when pooled sera from CVB3/M-protected mice were used to probe a Western blot of pancreatic proteins, numerous proteins were detected, whereas only one band was detected by sera from CVB3/GA-protected mice. No proteins were detected by sera from diabetic or normal mice. Cumulatively, these data do not support the hypothesis that CVB are causative agents of T1D. To the contrary, CVB infections provide significant protection from T1D onset in NOD mice. Possible mechanisms by which this virus-induced protection may occur are discussed.
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Kemball, Christopher C., Stephanie Harkins, Jason K. Whitmire, Ralph Feuer, Claudia T. Flynn, and J. Lindsay Whitton. "Coxsackievirus B3 has profoundly different inhibitory effects on the MHC class I and class II antigen presentation pathways (131.2)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 131.2. http://dx.doi.org/10.4049/jimmunol.182.supp.131.2.
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Abstract Coxsackievirus B (CVB) infections cause considerable morbidity and mortality, and strategies to treat or prevent CVB-associated disease may benefit from a clearer understanding of the host immune response to virus infection. CVB3 induces minimal endogenous naïve CD8 and CD4 T cell responses, possibly because viral antigen (Ag) presentation is extremely limited. Several CVB3 proteins are known to cooperatively downregulate MHC class I on infected cells in vitro. In this study, we used transgenic (Tg) CD4 and CD8 T cells as sensors to evaluate viral Ag presentation by the MHC class I and class II pathways in vivo. Our analysis revealed a striking difference in Tg T cell responses: CD4 Tg T cells proliferated in CVB3-infected mice whereas CD8 Tg T cells failed to divide. Moreover, virus infection generated multi-functional memory CD4 T cells, which expanded dramatically following challenge infection, and rapidly differentiated into secondary effector Th1 cells. Although naïve CD8 Tg T cells were unresponsive to CVB3, they persisted in the host and responded vigorously when stimulated by a different virus encoding their cognate Ag. These data suggest that CVB3 utilizes a powerful immune evasion strategy in vivo that differentially affects the two Ag presentation pathways, and that this difference regulates the host's capacity to mount CD4 and CD8 T cell responses. This work was supported by NIH R01 AI42314 and T32 NS41219.
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Gao, Guang, Jerry Wong, Jingchun Zhang, Ivy Mao, Jayant Shravah, Yan Wu, Allen Xiao, Xiaotao Li, and Honglin Luo. "Proteasome Activator REGγ Enhances Coxsackieviral Infection by Facilitating p53 Degradation." Journal of Virology 84, no. 21 (August 18, 2010): 11056–66. http://dx.doi.org/10.1128/jvi.00008-10.
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ABSTRACT Coxsackievirus B3 (CVB3) is a small RNA virus associated with diseases such as myocarditis, meningitis, and pancreatitis. We have previously demonstrated that proteasome inhibition reduces CVB3 replication and attenuates virus-induced myocarditis. However, the underlying mechanisms by which the ubiquitin/proteasome system regulates CVB replication remain unclear. In this study, we investigated the role of REGγ, a member of the 11S proteasome activator, in CVB3 replication. We showed that overexpression of REGγ promoted CVB3 replication but that knockdown of REGγ led to reduced CVB3 replication. We further demonstrated that REGγ-mediated p53 proteolysis contributes, as least in part, to the proviral function of REGγ. Although total protein levels of REGγ remained unaltered after CVB3 infection, virus infection induced a redistribution of REGγ from the nucleus to the cytoplasm, rendering an opportunity for a direct interaction of REGγ with viral proteins and/or host proteins (e.g., p53), which controls viral growth and thereby enhances viral infectivity. Further analyses suggested a potential modification of REGγ by SUMO following CVB3 infection, which was verified by both in vitro and in vivo sumoylation assays. Sumoylation of REGγ may play a role in its nuclear export during CVB3 infection. Taken together, our results present the first evidence that the host REGγ pathway is utilized and modified during CVB3 infection to promote efficient viral replication.
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Lasrado, Ninaad, Arunakumar Gangaplara, Rajkumar Arumugam, Chandirasegaran Massilamany, Sayli Pokal, Yuzhen Zhou, Shi-Hua Xiang, David Steffen, and Jay Reddy. "Identification of Immunogenic Epitopes That Permit the Detection of Antigen-Specific T Cell Responses in Multiple Serotypes of Group B Coxsackievirus Infections." Viruses 12, no. 3 (March 21, 2020): 347. http://dx.doi.org/10.3390/v12030347.
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Coxsackievirus group B (CVB) contains six serotypes that can affect various organs. Some of these organ-specific diseases such as myocarditis and pancreatitis can be caused by more than one serotype. Thus, development of immunological tools common to multiple serotypes is desired. This is especially critical for analyzing antigen-specific T cell responses at a single cell level. To this end, we made efforts to identify the immunogenic epitopes of CVB3 leading us to localize three T cell epitopes within the viral protein 1 (VP1) namely, VP1 681–700, VP1 721–740 and VP1 771–790. First, we confirmed their immunogenicity in the immunization settings. Second, we sought to verify the ability of VP1 epitopes to bind major histocompatibility complex (MHC) class II (IAk) molecules. Third, we created MHC class II (IAk) dextramers and tetramers and ascertained the T cell responses to be antigen-specific. Fourth, we analyzed the T cell responses in animals infected with CVB3 and noted the magnitude of antigen-specific T cell responses occurring in the order of VP1 721–740 and VP1 681–700 followed by VP1 771–790 as verified by proliferation assay and IAk tetramer staining. All epitopes induced interferon (IFN)-γ as a major cytokine. Finally, we investigated whether the VP1 tools generated for CVB3 can also be used to verify T cell responses in infections caused by other serotypes. To this end, we established the CVB4 infection model in A/J mice and found that the CVB4 infection led to the induction of IFN-γ-producing T cell responses primarily for VP1 721–740 and VP1 681–700. Thus, the VP1-specific tools, particularly IAk tetramers can be used to monitor anti-viral T cell responses in multiple CVB serotypes.
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Lasrado, Ninaad, Mahima T. Rasquinha, Meghna Sur, Arunakumar Gangaplara, Chandirasegaran Massilamany, Rajkumar Arumugam, David Steffen, and Jay Reddy. "A live-attenuated mutant CVB3 vaccine virus protects against multiple coxsackievirus B infections." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 64.11. http://dx.doi.org/10.4049/jimmunol.208.supp.64.11.
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Abstract Group B Coxsackieviruses (CVB) contains six serotypes, namely CVB1 through CVB6, affecting various organs. But, no vaccines are currently available to prevent these infections. We recently derived a live attenuated vaccine virus termed mutant (Mt) 10 encoding a single amino acid substitution H790A within the viral protein 1 (VP1) of the CVB3 viral canyon region. This virus could prevent myocarditis and pancreatitis caused by both homologous (CVB3) and heterologous (CVB4) serotypes in A/J mice. Mechanistically, we noted that the vaccine virus induces cross-reactive neutralizing antibodies that skewed towards mainly IgG isotypes. Similarly, by using major histocompatibility complex class II dextramers and tetramers for various VP1 epitopes, we demonstrated that the vaccine recipients develop antigen-specific T cell responses producing preferentially interferon-γ responses. Furthermore, our preliminary studies revealed that the vaccine virus could prevent the progression of diabetes-induced by CVB4 in the non-obese diabetic mice. Together, our data suggest that the Mt10 vaccine can prevent infections caused by multiple CVB serotypes, paving the way for developing monovalent CVB vaccines to prevent heart and pancreatic diseases of enteroviral origin. This work was supported by The Transformational Grant from the American Heart Association (18TPA34170206)
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Nakamura, Yuko, Akikazu Sakudo, Keiichi Saeki, Tomomi Kaneko, Yoshitsugu Matsumoto, Antonio Toniolo, Shigeyoshi Itohara, and Takashi Onodera. "Transfection of prion protein gene suppresses coxsackievirus B3 replication in prion protein gene-deficient cells." Journal of General Virology 84, no. 12 (December 1, 2003): 3495–502. http://dx.doi.org/10.1099/vir.0.19222-0.
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The susceptibility of prion protein gene (Prnp)-null cells to coxsackievirus B3 (CVB3) was investigated. Primary cultures of murine Prnp −/− brain cells were more sensitive to CVBs than corresponding cells from wild-type mice. The viral susceptibility of a Prnp-null cell line (HpL3-4) derived from the murine hippocampus was compared with that of two established cell lines (HeLa and HEp-2) that are widely employed for CVB3 studies. After infection with CVB3, HpL3-4 cells showed a very rapid and complete cytopathic effect (CPE). CPE developed earlier and viruses replicated at higher titres in HpL3-4 cells compared with HeLa and HEp-2 cells. Under a semi-solid medium, plaques developed rapidly in CVB3-infected HpL3-4 cells. To confirm the effect of Prnp on virus infection, a Prnp −/− cell line and a Prnp-transfected neuronal cell line were analysed. The replication and release of infectious particles of CVB3 in Prnp −/− cells were significantly more effective than those of the Prnp-transfected cell line. Levels of type I interferon (IFN) after CVB3 infection were higher in the Prnp-transfected cell line than in Prnp −/− cells, whereas apoptotic cells were more obvious in the Prnp −/− cells than in those of the Prnp-transfected cell line. These findings suggest that the absence of Prnp retards the induction of CVB3-induced IFNs, resulting in an enhanced CVB3 production and apoptotic cell death. Furthermore, our data indicate that the HpL3-4 cell line may provide a novel and sensitive system for isolation of CVB3 from clinical specimens.
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Pinkert, Sandra, Carsten Röger, Jens Kurreck, Jeffrey M. Bergelson, and Henry Fechner. "The Coxsackievirus and Adenovirus Receptor: Glycosylation and the Extracellular D2 Domain Are Not Required for Coxsackievirus B3 Infection." Journal of Virology 90, no. 12 (March 30, 2016): 5601–10. http://dx.doi.org/10.1128/jvi.00315-16.
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ABSTRACTThe coxsackievirus and adenovirus receptor (CAR) is a member of the immunoglobulin superfamily (IgSF) and functions as a receptor for coxsackie B viruses (CVBs). The extracellular portion of CAR comprises two glycosylated immunoglobulin-like domains, D1 and D2. CAR-D1 binds to the virus and is essential for virus infection; however, it is not known whether D2 is also important for infection, and the role of glycosylation has not been explored. To understand the function of these structural components in CAR-mediated CVB3 infection, we generated a panel of human (h) CAR deletion and substitution mutants and analyzed their functionality as CVB receptors, examining both virus binding and replication. Lack of glycosylation of the CAR-D1 or -D2 domains did not adversely affect CVB3 binding or infection, indicating that the glycosylation of CAR is not required for its receptor functions. Deletion of the D2 domain reduced CVB3 binding, with a proportionate reduction in the efficiency of virus infection. Replacement of D2 with the homologous D2 domain from chicken CAR, or with the heterologous type C2 immunoglobulin-like domain from IgSF11, another IgSF member, fully restored receptor function; however, replacement of CAR-D2 with domains from CD155 or CD80 restored function only in part. These data indicate that glycosylation of the extracellular domain of hCAR plays no role in CVB3 receptor function and that CAR-D2 is not specifically required. The D2 domain may function largely as a spacer permitting virus access to D1; however, the data may also suggest that D2 affects virus binding by influencing the conformation of D1.IMPORTANCEAn important step in virus infection is the initial interaction of the virus with its cellular receptor. Although the role in infection of the extracellular CAR-D1, cytoplasmic, and transmembrane domains have been analyzed extensively, nothing is known about the function of CAR-D2 and the extracellular glycosylation of CAR. Our data indicate that glycosylation of the extracellular CAR domain has only minor importance for the function of CAR as CVB3 receptor and that the D2 domain is not essential per se but contributes to receptor function by promoting the exposure of the D1 domain on the cell surface. These results contribute to our understanding of the coxsackievirus-receptor interactions.
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Chehadeh, Wassim, Julie Kerr-Conte, François Pattou, Gunar Alm, Jean Lefebvre, Pierre Wattré, and Didier Hober. "Persistent Infection of Human Pancreatic Islets by Coxsackievirus B Is Associated with Alpha Interferon Synthesis in β Cells." Journal of Virology 74, no. 21 (November 1, 2000): 10153–64. http://dx.doi.org/10.1128/jvi.74.21.10153-10164.2000.
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ABSTRACT The interactions of coxsackievirus B3 (CVB3), CVB4E2 (diabetogenic), and CVB4JBV (nondiabetogenic) strains with human pancreatic islets from eight adult brain-dead donors were investigated. Persistent replication of viruses in human islets was proved by detection of viral RNA by in situ hybridization, VP1 capsid protein by immunofluorescence (IF) staining, negative-strand viral RNA by reverse transcription-PCR in extracted RNA from islets, and release of infectious particles up to 30 days after infection without obvious cytolysis. By double IF staining, glucagon-containing α cells and insulin-containing β cells were shown to be susceptible to CVB. The persistence of CVB3 and CVB4 in islet cells was associated with the chronic synthesis of alpha interferon (IFN-α), as evidenced by the detection of IFN-α mRNA and immunoreactive IFN-α with antiviral activity. By double IF staining, IFN-α was detected in insulin-producing β cells only. Experiments with neutralizing anti-coxsackievirus and adenovirus receptor (CAR) antibodies provided evidence that CAR was expressed by α and β cells and that it played a role in the infection of these cells with CVB and the consecutive IFN-α expression in β cells. The viral replication and the expression of IFN-α in islets were not restricted to the CVB4E2 diabetogenic strain and did not depend on the genetic background of the host. The neutralization of endogenous IFN-α significantly enhanced the CVB replication in islet cells and resulted in rapid destruction of islets. Thus, human β cells can harbor a persistent CVB infection, and CVB-induced IFN-α plays a role in the initiation and/or maintenance of chronic CVB infection in human islets.
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Weller, A. H., K. Simpson, M. Herzum, N. Van Houten, and S. A. Huber. "Coxsackievirus-B3-induced myocarditis: virus receptor antibodies modulate myocarditis." Journal of Immunology 143, no. 6 (September 15, 1989): 1843–50. http://dx.doi.org/10.4049/jimmunol.143.6.1843.
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Abstract Two variants of coxsackievirus group B, type 3 (CVB3) differ in ability to induce myocarditis in Balb/cCUM mice. Infection with the highly pathogenic variant (CVB3M) stimulates autoimmunity to normal cardiocyte antigens, and tissue injury results primarily from an autoreactive cytolytic T lymphocyte (ACTL). Animals infected with the less pathogenic CVB3o variant do not develop ACTL, although CVB3o replicates to high titers in the heart and polyclonal neutralizing antisera fail to distinguish between the two variant virions. The present study uses two IgM mAb derived by fusing spleen cells from CVB3M-infected mice with NS-1 cells. These mAb investigate important differences between the virus variants that may explain why only selected infections trigger autoimmunity. mAb 8A6 is a virus-neutralizing antibody that prevents infection of HeLa cells and cultured cardiocytes by attaching to the virus. mAb 10A1 also interferes with infection but presumably reacts to the virus receptor on the susceptible cells and shows little or no binding to the virions. While 8A6 is equally effective in neutralizing both CVB3o and CVB3M, suggesting that antigenic epitopes on both variants are either identical or highly cross-reactive, 10A1 distinguishes between the variants, suggesting that the pathogenic and less pathogenic viruses use distinct cell surface receptors. Competitive binding studies using radiolabeled CVB3M and either of the unlabeled variants confirm this hypothesis. Both mAb effectively prevent CVB3M-induced cardiac damage in vivo. mAb 10A1 also inhibits autoreactive ACTL lysis of cardiocytes, indicating that the autoimmune effectors may recognize the virus receptor, and that the receptor utilized by a virus may prove important in triggering auto-sensitization.
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Kraft, Lisa, Martina Sauter, Guiscard Seebohm, and Karin Klingel. "In Vitro Model Systems of Coxsackievirus B3-Induced Myocarditis: Comparison of Commonly Used Cell Lines and Characterization of CVB3-Infected iCell® Cardiomyocytes." Viruses 13, no. 9 (September 14, 2021): 1835. http://dx.doi.org/10.3390/v13091835.
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Coxsackievirus B3 (CVB3) belongs to the enteroviruses, which are a well-known cause of acute and chronic myocarditis, primarily infecting cardiac myocytes. As primary human cardiomyocytes are difficult to obtain, viral myocarditis is quite frequently studied in vitro in different non-cardiac and cardiac-like cell lines. Recently, cardiomyocytes that have been differentiated from human-induced pluripotent stem cells have been described as a new model system to study CVB3 infection. Here, we compared iCell® Cardiomyocytes with other cell lines that are commonly used to study CVB3 infection regarding their susceptibility and patterns of infection and the mode of cell death. iCell® Cardiomyocytes, HeLa cells, HL-1 cells and H9c2 cells were infected with CVB3 (Nancy strain). The viral load, CVB3 RNA genome localization, VP1 expression (including the intracellular localization), cellular morphology and the expression of cell death markers were compared. The various cell lines clearly differed in their permissiveness to CVB3 infection, patterns of infection, viral load, and mode of cell death. When studying the mode of cell death of CVB3-infected iCell® Cardiomyocytes in more detail, especially regarding the necroptosis key players RIPK1 and RIPK3, we found that RIPK1 is cleaved during CVB3 infection. iCell® Cardiomyocytes represent well the natural host of CVB3 in the heart and are thus the most appropriate model system to study molecular mechanisms of CVB3-induced myocarditis in vitro. Doubts are raised about the suitability of commonly used cell lines such as HeLa cells, HL-1 cells and H9c2 cells to evaluate molecular pathways and processes occurring in vivo in enteroviral myocarditis.
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Patel, Kunal P., Carolyn B. Coyne, and Jeffrey M. Bergelson. "Dynamin- and Lipid Raft-Dependent Entry of Decay-Accelerating Factor (DAF)-Binding and Non-DAF-Binding Coxsackieviruses into Nonpolarized Cells." Journal of Virology 83, no. 21 (August 26, 2009): 11064–77. http://dx.doi.org/10.1128/jvi.01016-09.
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ABSTRACT Group B coxsackieviruses (CVB) use the CVB and adenovirus receptor (CAR) to enter and infect cells. Some CVB also bind to decay-accelerating factor (DAF), but that interaction alone is insufficient for infection. We previously found that CVB3 entry into polarized human intestinal cells (Caco-2) occurs by a caveolin-dependent but dynamin-independent mechanism that requires DAF-mediated tyrosine kinase signals. In this study, we examined how CVB enter and infect nonpolarized HeLa cells and how DAF binding affects these processes. Using immunofluorescence microscopy and a combination of dominant-negative proteins, small interfering RNAs, and drugs targeting specific endocytic pathways, we found that both DAF-binding and non-DAF-binding virus isolates require dynamin and lipid rafts to enter and infect cells. Unlike what we observed in Caco-2 cells, CVB3 entered HeLa cells with CAR. We found no role for clathrin, endosomal acidification, or caveolin. Inhibition of tyrosine kinases blocked an early event in infection but did not prevent entry of virus into the cell. These results indicate that CVB3 entry into nonpolarized HeLa cells differs significantly from entry into polarized Caco-2 cells and is not influenced by virus binding to DAF.
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Goodfellow, Ian G., David J. Evans, Anna M. Blom, Dave Kerrigan, J. Scott Miners, B. Paul Morgan, and O. Brad Spiller. "Inhibition of Coxsackie B Virus Infection by Soluble Forms of Its Receptors: Binding Affinities, Altered Particle Formation, and Competition with Cellular Receptors." Journal of Virology 79, no. 18 (September 15, 2005): 12016–24. http://dx.doi.org/10.1128/jvi.79.18.12016-12024.2005.
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ABSTRACT We previously reported that soluble decay-accelerating factor (DAF) and coxsackievirus-adenovirus receptor (CAR) blocked coxsackievirus B3 (CVB3) myocarditis in mice, but only soluble CAR blocked CVB3-mediated pancreatitis. Here, we report that the in vitro mechanisms of viral inhibition by these soluble receptors also differ. Soluble DAF inhibited virus infection through the formation of reversible complexes with CVB3, while binding of soluble CAR to CVB induced the formation of altered (A) particles with a resultant irreversible loss of infectivity. A-particle formation was characterized by loss of VP4 from the virions and required incubation of CVB3-CAR complexes at 37°C. Dimeric soluble DAF (DAF-Fc) was found to be 125-fold-more effective at inhibiting CVB3 than monomeric DAF, which corresponded to a 100-fold increase in binding affinity as determined by surface plasmon resonance analysis. Soluble CAR and soluble dimeric CAR (CAR-Fc) bound to CVB3 with 5,000- and 10,000-fold-higher affinities than the equivalent forms of DAF. While DAF-Fc was 125-fold-more effective at inhibiting virus than monomeric DAF, complement regulation by DAF-Fc was decreased 4 fold. Therefore, while the virus binding was a cooperative event, complement regulation was hindered by the molecular orientation of DAF-Fc, indicating that the regions responsible for complement regulation and virus binding do not completely overlap. Relative contributions of CVB binding affinity, receptor binding footprint on the virus capsid, and induction of capsid conformation alterations for the ability of cellular DAF and CAR to act as receptors are discussed.
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Evstropov, A. N., L. G. Burova, O. R. Greck, L. N. Zakharova, and T. A. Volkhonskay. "The employment of polyphenol complexes extracted from Pеnthaphylloides fruticosa (L.) O. Scwarz for prophylactic of Coxsackie-virus infection." Bulletin of Siberian Medicine 1, no. 4 (December 30, 2002): 27–31. http://dx.doi.org/10.20538/1682-0363-2002-4-27-31.
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In the present work the antiviral activity of water extract, received from Pеnthaphylloides fruticosa (L.) O. Scwarz, against Enteroviruses Coxsackie B (CVB) was studied. The maximal intoxic dose of the preparation for the cell-culture (CC) Нер-2 was 1500 mg/ml. It was found, that a preliminary processing of the CC by substance 24 hours before the virus contamination suppresses the virus reproduction in minimal inhibition doses 31 mg/ml — for CVB1-5 and 63 mg/ml — for CVB6. After that, the prophylactic action of the water extract against CVB3 was showed in experimental infection in newborn mice. It maximal intoxic doses for BALB/c mice is 100 mg/kg. The scheme with the preliminary inoculation of pregnant mice by 40 mg/kg of water extract within 3—5 days and following contamination of new-born animals by 100 DLM of virus, showed positive results: increase percent of survival and average life duration, improving of weight dynamics, decrease of virus accumulation level in tissues of brain, liver, heart. The received results determine good prospects for further investigation of water extract from Pеnthaphylloides fruticosa as prophylactic antiviral remedy.
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Si, Xiaoning, Honglin Luo, Andrew Morgan, Jingchun Zhang, Jerry Wong, Ji Yuan, Mitra Esfandiarei, Guang Gao, Caroline Cheung, and Bruce M. McManus. "Stress-Activated Protein Kinases Are Involved in Coxsackievirus B3 Viral Progeny Release." Journal of Virology 79, no. 22 (November 15, 2005): 13875–81. http://dx.doi.org/10.1128/jvi.79.22.13875-13881.2005.
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ABSTRACT Stress-activated protein kinases (SAPKs), consisting of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), are activated upon various environmental stimuli, including viral infections. Cellular survival and death signaling events following coxsackievirus B3 (CVB3) infection have been studied in relationship to viral replication, but the role of SAPKs has not been scrutinized. In this study, we found that the phosphorylation of JNK1/2 and p38 MAPK was increased during active replication of CVB3 and that their phosphorylation was independent of CVB3-induced caspase activation or production of reactive oxygen species. The roles of these kinases in CVB3 infection were further evaluated using specific inhibitors: SP600125 for JNK1/2 and SB203580 for p38 MAPK. JNK1/2 inhibitors reduced CVB3-induced phosphorylation of activating transcription factor 2, and the p38 MAPK inhibitor reduced CVB3-induced phosphorylation of heat shock protein 27. Although inhibition of these kinases by specific inhibitors did not affect CVB3 viral protein synthesis, inhibition of p38 MAPK but not of JNK1/2 resulted in significant reduction of viral progeny release, suppression of CVB3-induced cell death, and blockage of CVB3-induced caspase-3 activation in infected cells. We conclude that SAPK pathways play critical roles in the life cycle of CVB3, particularly in viral progeny release.
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Kim, Sun-Mi, Jung-Hyun Park, Sun-Ku Chung, Joo-Young Kim, Ha-Young Hwang, Kwang-Chul Chung, Inho Jo, Sang-Ick Park, and Jae-Hwan Nam. "Coxsackievirus B3 Infection Induces cyr61 Activation via JNK To Mediate Cell Death." Journal of Virology 78, no. 24 (December 15, 2004): 13479–88. http://dx.doi.org/10.1128/jvi.78.24.13479-13488.2004.
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ABSTRACT Coxsackievirus B3 (CVB3), an enterovirus in the Picornavirus family, is the most common human pathogen associated with myocarditis and idiopathic dilated cardiomyopathy. We found upregulation of the cysteine-rich protein gene (cyr61) after CVB3 infection in HeLa cells with a cDNA microarray approach, which is confirmed by Northern blot analysis. It is also revealed that the extracellular amount of Cyr61 protein was increased after CVB3 infection in HeLa cells. cyr61 is an early-transcribed gene, and the Cyr61 protein is secreted into the extracellular matrix. Its function is related to cell adhesion, migration, and neuronal cell death. Here, we show that activation of the cyr61 promoter by CVB3 infection is dependent on JNK activation induced by CVB3 replication and viral protein expression in infected cells. To explore the role of Cyr61 protein in infected HeLa cells, we transiently overexpressed cyr61 and infected HeLa cells with CVB3. This increased CVB3 growth in the cells and promoted host cell death by viral infection, whereas down-expression of cyr61 with short interfering RNA reduced CVB3 growth and showed resistance to cell death by CVB3 infection. In conclusion, we have demonstrated a new role for cyr61 in HeLa cells infected with CVB3, which is associated with the cell death induced by virus infection. These data thus expand our understanding of the physiological functions of cyr61 in virus-induced cell death and provide new insights into the cellular factors involved.
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Zhang, Huifang M., Xin Ye, Yue Su, Ji Yuan, Zhen Liu, David A. Stein, and Decheng Yang. "Coxsackievirus B3 Infection Activates the Unfolded Protein Response and Induces Apoptosis through Downregulation of p58IPK and Activation of CHOP and SREBP1." Journal of Virology 84, no. 17 (June 16, 2010): 8446–59. http://dx.doi.org/10.1128/jvi.01416-09.
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ABSTRACT Cardiomyocyte apoptosis is a hallmark of coxsackievirus B3 (CVB3)-induced myocarditis. We used cardiomyocytes and HeLa cells to explore the cellular response to CVB3 infection, with a focus on pathways leading to apoptosis. CVB3 infection triggered endoplasmic reticulum (ER) stress and differentially regulated the three arms of the unfolded protein response (UPR) initiated by the proximal ER stress sensors ATF6a (activating transcription factor 6a), IRE1-XBP1 (X box binding protein 1), and PERK (PKR-like ER protein kinase). Upon CVB3 infection, glucose-regulated protein 78 expression was upregulated, and in turn ATF6a and XBP1 were activated via protein cleavage and mRNA splicing, respectively. UPR activity was further confirmed by the enhanced expression of UPR target genes ERdj4 and EDEM1. Surprisingly, another UPR-associated gene, p58IPK, which often is upregulated during infections with other types of viruses, was downregulated at both mRNA and protein levels after CVB3 infection. These findings were observed similarly for uninfected Tet-On HeLa cells induced to overexpress ATF6a or XBP1. In exploring potential connections between the three UPR pathways, we found that the ATF6a-induced downregulation of p58IPK was associated with the activation of PKR (PERK) and the phosphorylation of eIF2α, suggesting that p58IPK, a negative regulator of PERK and PKR, mediates cross-talk between the ATF6a/IRE1-XBP1 and PERK arms. Finally, we found that CVB3 infection eventually produced the induction of the proapoptoic transcription factor CHOP and the activation of SREBP1 and caspase-12. Taken together, these data suggest that CVB3 infection activates UPR pathways and induces ER stress-mediated apoptosis through the suppression of P58IPK and induction/activation of CHOP, SREBP1, and caspase-12.
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Henke, A., C. Mohr, H. Sprenger, C. Graebner, A. Stelzner, M. Nain, and D. Gemsa. "Coxsackievirus B3-induced production of tumor necrosis factor-alpha, IL-1 beta, and IL-6 in human monocytes." Journal of Immunology 148, no. 7 (April 1, 1992): 2270–77. http://dx.doi.org/10.4049/jimmunol.148.7.2270.
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Abstract Infections by coxsackievirus B3 (CVB3) have previously been shown to cause acute and chronic myocarditis characterized by a heavy mononuclear leukocyte infiltration and myocyte necrosis. Because clinical and experimental evidence suggested that cardiac damage may result from immunologic rather than viral mechanisms, we examined in this study the in vitro interaction of CVB3 with human monocytes. CVB3 was capable of infecting freshly harvested monocytes as revealed by immunofluorescence and release of infectious virus particles. Virus infection did not reduce monocyte viability but, on the contrary, enhanced spreading and adherence. In a dose-dependent manner, CVB3 stimulated the release of cytokines from monocytes. Whereas a potent production of TNF-alpha, IL-1 beta, and IL-6 was dependent on exposure to infectious CVB3, IFN release was also induced by UV-inactivated virus. On a molecular level, CVB3 stimulated cytokine gene expression as shown by a marked TNF-alpha, IL-1 beta, and IL-6 mRNA accumulation. Supernatants of CVB3-infected monocytes displayed cytotoxic activity against Girardi heart cells which could be abrogated by an anti-TNF-alpha antiserum. These data suggest that CVB3-induced cytokine release from monocytes may participate in virus-induced organ damage such as myocarditis, which may either occur by a direct cytotoxicity of cytokines or by activation of cytotoxic lymphocytes.
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Zautner, A. E., U. Körner, A. Henke, C. Badorff, and M. Schmidtke. "Heparan Sulfates and Coxsackievirus-Adenovirus Receptor: Each One Mediates Coxsackievirus B3 PD Infection." Journal of Virology 77, no. 18 (September 15, 2003): 10071–77. http://dx.doi.org/10.1128/jvi.77.18.10071-10077.2003.
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ABSTRACT Amino acid exchanges in the virus capsid protein VP1 allow the coxsackievirus B3 variant PD (CVB3 PD) to replicate in decay accelerating factor (DAF)-negative and coxsackievirus-adenovirus receptor (CAR)-negative cells. This suggests that molecules other than DAF and CAR are involved in attachment of this CVB3 variant to cell surfaces. The observation that productive infection associated with cytopathic effect occurred in Chinese hamster ovary (CHO-K1) cells, whereas heparinase-treated CHO-K1 cells, glucosaminoglycan-negative pgsA-745, heparan sulfate (HS)-negative pgsD-677, and pgsE-606 cells with significantly reduced N-sulfate expression resist CVB3 PD infection, indicates a critical role of highly sulfated HS. 2-O-sulfate-lacking pgsF-17 cells represented the cell line with minimum HS modifications susceptible for CVB3 PD. Inhibition of virus replication in CHO-K1 cells by polycationic compounds, pentosan polysulfate, lung heparin, and several intestinal but not kidney HS supported the hypothesis that CVB3 PD uses specific modified HS for entry. In addition, recombinant human hepatocyte growth factor blocked CVB3 PD infection. However, CAR also mediates CVB3 PD infection, because this CVB3 variant replicates in HS-lacking but CAR-bearing Raji cells, infection could be prevented by pretreatment of cells with CAR antibody, and HS-negative pgsD-677 cells transfected with CAR became susceptible for CVB3 PD. These results demonstrate that the amino acid substitutions in the viral capsid protein VP1 enable CVB3 PD to use specific modified HS as an entry receptor in addition to CAR.
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Shim, Seung-Hyun, Dae-Sun Kim, and Jae-Hwan Nam. "Coxsackievirus B3 regulates T cell infiltration by LFA-1 modification through Rap1 activation (P5075)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 129.2. http://dx.doi.org/10.4049/jimmunol.190.supp.129.2.
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Abstract Coxsackievirus B3 (CVB3) infection has the potential to induce myocarditis. The following may be the mechanisms of CVB3-induced pathogenesis: viral infection directly causes injuries to cardiomyocytes through viral cytopathic effect and virus-activated T cell infiltration indirectly causes injuries to cardiomyocytes through inflammation. However, the detailed mechanism of T cell infiltration remains unknown. The present study observed that infiltrated T cells could be detected in the hearts of CVB3-infected mice. Meanwhile, attenuated CVB3 (YYFF) did not elicit T cell infiltration in infected mouse hearts. Rap-1, Ras family of small GTPases, is a critical regulator of T cell activation. CVB3 infection was found to activate Rap1 through cAMP induction. The downstream molecules of Rap1, ERK and p-CREB, which are involved in T cell activation and differentiation, were also activated after CVB3 infection. However, this result did not occur in the case of YYFF. This Rap-1 activation leads to an active form of LFA-1 on T cells that can be bound to intracellular adhesion molecule-1 (ICAM-1) on myocytes for T cell infiltration after CVB3 infection. This mechanism of CVB3-induced T cell infiltration may contribute to be a potential therapeutic agent for virus-induced myocarditis. Keywords: Coxsackievirus B3, YYFF, LFA-1
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Yuan, Ji, David A. Stein, Travis Lim, Dexin Qiu, Shaun Coughlin, Zhen Liu, Yinjing Wang, et al. "Inhibition of Coxsackievirus B3 in Cell Cultures and in Mice by Peptide-Conjugated Morpholino Oligomers Targeting the Internal Ribosome Entry Site." Journal of Virology 80, no. 23 (September 20, 2006): 11510–19. http://dx.doi.org/10.1128/jvi.00900-06.
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ABSTRACT Coxsackievirus B3 (CVB3) is a primary cause of viral myocarditis, yet no effective therapeutic against CVB3 is available. Nucleic acid-based interventional strategies against various viruses, including CVB3, have shown promise experimentally, but limited stability and inefficient delivery in vivo remain as obstacles to their potential as therapeutics. We employed phosphorodiamidate morpholino oligomers (PMO) conjugated to a cell-penetrating arginine-rich peptide, P007 (to form PPMO), to address these issues. Eight CVB3-specific PPMO were evaluated with HeLa cells and HL-1 cardiomyocytes in culture and in a murine infection model. One of the PPMO (PPMO-6), designed to target a sequence in the 3′ portion of the CVB3 internal ribosomal entry site, was found to be especially potent against CVB3. Treatment of cells with PPMO-6 prior to CVB3 infection produced an approximately 3-log10 decrease in viral titer and largely protected cells from a virus-induced cytopathic effect. A similar antiviral effect was observed when PPMO-6 treatment began shortly after the virus infection period. A/J mice receiving intravenous administration of PPMO-6 once prior to and once after CVB3 infection showed an ∼2-log10-decreased viral titer in the myocardium at 7 days postinfection and a significantly decreased level of cardiac tissue damage, compared to the controls. Thus, PPMO-6 provided potent inhibition of CVB3 amplification both in cell cultures and in vivo and appears worthy of further evaluation as a candidate for clinical development.
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Luo, Honglin, Jingchun Zhang, Frank Dastvan, Bobby Yanagawa, Michael A. Reidy, Huifang M. Zhang, Decheng Yang, Janet E. Wilson, and Bruce M. McManus. "Ubiquitin-Dependent Proteolysis of Cyclin D1 Is Associated with Coxsackievirus-Induced Cell Growth Arrest." Journal of Virology 77, no. 1 (January 1, 2003): 1–9. http://dx.doi.org/10.1128/jvi.77.1.1-9.2003.
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ABSTRACT Coxsackievirus group B3 (CVB3) replication is influenced by host cell cycle status. However, the effect of CVB3 infection on cell cycle regulation and the mechanisms involved are not precisely defined. In this study, we examined cell cycle progression and regulation when the infection was initiated in late G1 phase of the cell cycle. Analysis of cellular DNA synthesis in infected cells by thymidine incorporation assays showed a significant reduction in [3H]thymidine uptake compared to that of sham-infected cells. To further clarify the effects of CVB3 on the host cell cycle, we examined the cell cycle regulatory proteins involved in G1 progression and G1/S transition. Infection resulted in dephosphorylation of retinoblastoma protein and reduced G1 cyclin-dependent kinase activities, accompanied by decreased levels of G1 cyclin protein expression (cyclin D1 and cyclin E). We further investigated the mechanisms by which CVB3 infection down-regulates cyclin D1 expression. Northern blotting showed that cyclin D1 mRNA levels were modestly increased following CVB3 infection, suggesting that cyclin D1 regulation occurs by a posttranscriptional mechanism. Viral infection resulted in only a 20 to 30% inhibition of cyclin D1 protein synthesis 3 h postinfection. However, the proteasome inhibitors MG132 and lactacystin prevent CVB3-induced cyclin D1 reduction, indicating that CVB3-induced down-regulation of cyclin D1 is facilitated by ubiquitin-proteasome proteolysis. Finally, using GSK3β pathway inhibitors, we showed that the reduction of cyclin D1 is GSK3β independent. Taken together, our results demonstrate that CVB3 infection disrupts host cell homeostasis by blocking the cell cycle at the G1/S boundary and induces cell cycle arrest in part through an increase in ubiquitin-dependent proteolysis of cyclin D1.
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Wang, Yan, Bo Gao, and Sidong Xiong. "Involvement of NLRP3 inflammasome in CVB3-induced viral myocarditis." American Journal of Physiology-Heart and Circulatory Physiology 307, no. 10 (November 15, 2014): H1438—H1447. http://dx.doi.org/10.1152/ajpheart.00441.2014.
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Viral myocarditis, which is most prevalently caused by coxsackievirus B3 (CVB3) infection, is a serious clinical condition characterized by cardiac inflammation. Inflammasome plays an essential role in the regulation of diverse inflammatory responses by serving as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of IL-1β. Although inflammasome has been reported to be crucial for the development of many inflammatory diseases, its role in the pathogenesis of viral myocarditis is still elusive. The present study aims to investigate whether CVB3 infection activates inflammasome and whether the activation of inflammasome contributes to CVB3-induced myocarditis. Our results showed that CVB3 infection induced inflammasome activation both in vitro and in vivo. With the inhibition of inflammasome activation, the severity of CVB3-induced myocarditis was significantly alleviated as evidenced by less weight loss, decreased serological indexes of creatine kinase and creatinekinase-MB activities, as well as less severe myocardial injury. Of importance, echocardiography results showed that inhibition of inflammasome activation also efficiently improved cardiac function as revealed by enhanced left ventricular ejection fraction and left ventricular fractional shortening. Despite that CVB3 infection significantly increased the expression of both retinoic acid-inducible gene 1 and NOD-like receptor family, pyrin domain containing 3 (NLRP3) in cardiac myocytes, CVB3-induced inflammasome activation was NLRP3-, but not retinoic acid-inducible gene 1, dependent. Further study showed that reactive oxygen species production and K+ efflux were critical for the activation of NLRP3 inflammasome upon CVB3 infection. Collectively, our study demonstrated a crucial role of the NLRP3 inflammasome in the pathogenesis of CVB3-induced myocarditis, and modulation of inflammasome activation might represent a promising therapeutic strategy for viral myocarditis.
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Kemball, Christopher C., Mehrdad Alirezaei, Claudia T. Flynn, Malcolm R. Wood, Stephanie Harkins, William B. Kiosses, and J. Lindsay Whitton. "Coxsackievirus Infection Induces Autophagy-Like Vesicles and Megaphagosomes in Pancreatic Acinar Cells In Vivo." Journal of Virology 84, no. 23 (September 22, 2010): 12110–24. http://dx.doi.org/10.1128/jvi.01417-10.
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ABSTRACT Autophagy can play an important part in protecting host cells during virus infection, and several viruses have developed strategies by which to evade or even exploit this homeostatic pathway. Tissue culture studies have shown that poliovirus, an enterovirus, modulates autophagy. Herein, we report on in vivo studies that evaluate the effects on autophagy of coxsackievirus B3 (CVB3). We show that in pancreatic acinar cells, CVB3 induces the formation of abundant small autophagy-like vesicles and permits amphisome formation. However, the virus markedly, albeit incompletely, limits the fusion of autophagosomes (and/or amphisomes) with lysosomes, and, perhaps as a result, very large autophagy-related structures are formed within infected cells; we term these structures megaphagosomes. Ultrastructural analyses confirmed that double-membraned autophagy-like vesicles were present in infected pancreatic tissue and that the megaphagosomes were related to the autophagy pathway; they also revealed a highly organized lattice, the individual components of which are of a size consistent with CVB RNA polymerase; we suggest that this may represent a coxsackievirus replication complex. Thus, these in vivo studies demonstrate that CVB3 infection dramatically modifies autophagy in infected pancreatic acinar cells.
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Oh, Soo-Jin, Jeong-An Gim, Jae Kyung Lee, Hosun Park, and Ok Sarah Shin. "Coxsackievirus B3 Infection of Human Neural Progenitor Cells Results in Distinct Expression Patterns of Innate Immune Genes." Viruses 12, no. 3 (March 17, 2020): 325. http://dx.doi.org/10.3390/v12030325.
Full textAbstract:
Coxsackievirus B3 (CVB3), a member of Picornaviridae family, is an important human pathogen that causes a wide range of diseases, including myocarditis, pancreatitis, and meningitis. Although CVB3 has been well demonstrated to target murine neural progenitor cells (NPCs), gene expression profiles of CVB3-infected human NPCs (hNPCs) has not been fully explored. To characterize the molecular signatures and complexity of CVB3-mediated host cellular responses in hNPCs, we performed QuantSeq 3′ mRNA sequencing. Increased expression levels of viral RNA sensors (RIG-I, MDA5) and interferon-stimulated genes, such as IFN-β, IP-10, ISG15, OAS1, OAS2, Mx2, were detected in response to CVB3 infection, while IFN-γ expression level was significantly downregulated in hNPCs. Consistent with the gene expression profile, CVB3 infection led to enhanced secretion of inflammatory cytokines and chemokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). Furthermore, we show that type I interferon (IFN) treatment in hNPCs leads to significant attenuation of CVB3 RNA copy numbers, whereas, type II IFN (IFN-γ) treatment enhances CVB3 replication and upregulates suppressor of cytokine signaling 1/3 (SOCS) expression levels. Taken together, our results demonstrate the distinct molecular patterns of cellular responses to CVB3 infection in hNPCs and the pro-viral function of IFN-γ via the modulation of SOCS expression.
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Dan, M., and J. K. Chantler. "A Genetically Engineered Attenuated Coxsackievirus B3 Strain Protects Mice against Lethal Infection." Journal of Virology 79, no. 14 (July 2005): 9285–95. http://dx.doi.org/10.1128/jvi.79.14.9285-9295.2005.
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ABSTRACT Coxsackievirus B3 (CVB3) is a common human pathogen that is endemic throughout the world. There is currently no vaccine available, although the virus is known to be highly lethal to newborns and has been associated with heart disease and pancreatitis in older children and adults. Previously, we showed that the virulence of CVB3 is reduced by a lysine-to-arginine substitution in the capsid protein VP2 (K2168R) or a glutamic acid-to-glycine substitution in VP3 (E3060G). In this report, we show that the double mutant virus CVB3(KR/EG) displays additional attenuation, particularly for the pancreas, in A/J mice. In addition, two other attenuating mutations have been identified in the capsid protein VP1. When either the aspartic acid residue D1155 was replaced with glutamic acid or the proline residue P1126 was replaced with methionine, the resulting mutant also possessed an attenuated phenotype. Moreover, when either of these mutations was incorporated into CVB3(KR/EG), the resulting triple mutant viruses, CVB3(KR/EG/DE) and CVB3(KR/EG/PM), were completely noncardiovirulent and caused only small foci of damage to the pancreas, even at a high dose. Both triple mutants were found to be immunogenic, and a single injection of young A/J mice with either was found to protect them from a subsequent lethal challenge with wild-type CVB3. These findings indicate that the triple mutants could be exploited for the development of a live attenuated vaccine against CVB3.
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Voss, Martin, Sandra Pinkert, Meike Kespohl, Niclas Gimber, Karin Klingel, Jan Schmoranzer, Michael Laue, Matthias Gaida, Peter-Michael Kloetzel, and Antje Beling. "A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence." Viruses 14, no. 4 (April 7, 2022): 769. http://dx.doi.org/10.3390/v14040769.
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Enteroviruses (EV) are implicated in an extensive range of clinical manifestations, such as pancreatic failure, cardiovascular disease, hepatitis, and meningoencephalitis. We recently reported on the biochemical properties of the highly conserved cysteine residue at position 38 (C38) of enteroviral protein 3A and demonstrated a C38-mediated homodimerization of the Coxsackievirus B3 protein 3A (CVB3-3A) that resulted in its profound stabilization. Here, we show that residue C38 of protein 3A supports the replication of CVB3, a clinically relevant member of the enterovirus genus. The infection of HeLa cells with protein 3A cysteine 38 to alanine mutants (C38A) attenuates virus replication, resulting in comparably lower virus particle formation. Consistently, in a mouse infection model, the enhanced virus propagation of CVB3-3A wt in comparison to the CVB3-3A[C38A] mutant was confirmed and found to promote severe liver tissue damage. In contrast, infection with the CVB3-3A[C38A] mutant mitigated hepatic tissue injury and ameliorated the signs of systemic inflammatory responses, such as hypoglycemia and hypothermia. Based on these data and our previous report on the C38-mediated stabilization of the CVB3-3A protein, we conclude that the highly conserved amino acid C38 in protein 3A enhances the virulence of CVB3.
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Shim, Seung-Hyun, Dae-Sun Kim, Whajung Cho, and Jae-Hwan Nam. "Coxsackievirus B3 regulates T-cell infiltration into the heart by lymphocyte function-associated antigen-1 activation via the cAMP/Rap1 axis." Journal of General Virology 95, no. 9 (September 1, 2014): 2010–18. http://dx.doi.org/10.1099/vir.0.065755-0.
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Coxsackievirus B3 (CVB3) infection can trigger myocarditis and can ultimately lead to dilated cardiomyopathy. It is known that CVB3-induced T-cell infiltration into cardiac tissues is one of the pathological factors causing cardiomyocyte injury by inflammation. However, the underlying mechanism for this remains unclear. We investigated the mechanism of T-cell infiltration by two types of CVB3: the H3 WT strain and the YYFF attenuated strain. T-cell activation was confirmed by changes in the distribution of lymphocyte function-associated antigen-1 (LFA-1). Finally, we identified which viral gene was responsible for LFA-1 activation. CVB3 could infect and activate T-cells in vivo and in vitro, and activated T-cells were detected in CVB3-infected mouse hearts. LFA-1 expressed on the surface of these T-cells had been activated through the cAMP/Rap1 pathway. Recombinant lentiviruses expressing VP2 of CVB3 could also induce LFA-1 activation via an increase in cAMP, whilst VP2 of YYFF did not. These results indicated that CVB3 infection increased cAMP levels and then activated Rap1 in T-cells. In particular, VP2, among the CVB3 proteins, might be critical for this activation. This VP2–cAMP–Rap1–LFA-1 axis could be a potential therapeutic target for treating CVB3-induced myocarditis.
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Luo, Honglin, Bobby Yanagawa, Jingchun Zhang, Zongshu Luo, Mary Zhang, Mitra Esfandiarei, Christopher Carthy, Janet E. Wilson, Decheng Yang, and Bruce M. McManus. "Coxsackievirus B3 Replication Is Reduced by Inhibition of the Extracellular Signal-Regulated Kinase (ERK) Signaling Pathway." Journal of Virology 76, no. 7 (April 1, 2002): 3365–73. http://dx.doi.org/10.1128/jvi.76.7.3365-3373.2002.
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ABSTRACT Coxsackievirus B3 (CVB3) is the most common human pathogen for viral myocarditis. We have previously shown that the signaling protein p21 ras GTPase-activating protein (RasGAP) is cleaved and that mitogen-activated protein kinases (MAPKs) ERK1/2 are activated in the late phase of CVB3 infection. However, the role of intracellular signaling pathways in CVB3-mediated myocarditis and the relative advantages of such pathways to host or virus remain largely unclear. In this study we extended our prior studies by examining the interaction between CVB3 replication and intracellular signaling pathways in HeLa cells. We observed that CVB3 infection induced a biphasic activation of ERK1/2, early transient activation versus late sustained activation, which were regulated by different mechanisms. Infection by UV-irradiated, inactivated virus capable of receptor binding and endocytosis triggered early ERK1/2 activation, but was insufficient to trigger late ERK1/2 activation. By using a general caspase inhibitor (zVAD.fmk) we further demonstrated that late ERK1/2 activation was not a result of CVB3-mediated caspase cleavage. Treatment of cells with U0126, a selective inhibitor of MAPK kinase (MEK), significantly inhibited CVB3 progeny release and decreased virus protein production. Furthermore, inhibition of ERK1/2 activation circumvented CVB3-induced apoptosis and viral protease-mediated RasGAP cleavage. Taken together, these data suggest that ERK1/2 activation is important for CVB3 replication and contributes to virus-mediated changes in host cells. Our findings demonstrate coxsackievirus takeover of a particular host signaling mechanism and uncover a prospective approach to stymie virus spread and preserve myocardial integrity.
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Wong, Jerry, Jingchun Zhang, Xiaoning Si, Guang Gao, Ivy Mao, Bruce M. McManus, and Honglin Luo. "Autophagosome Supports Coxsackievirus B3 Replication in Host Cells." Journal of Virology 82, no. 18 (July 2, 2008): 9143–53. http://dx.doi.org/10.1128/jvi.00641-08.
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ABSTRACT Recent studies suggest a possible takeover of host antimicrobial autophagy machinery by positive-stranded RNA viruses to facilitate their own replication. In the present study, we investigated the role of autophagy in coxsackievirus replication. Coxsackievirus B3 (CVB3), a picornavirus associated with viral myocarditis, causes pronounced intracellular membrane reorganization after infection. We demonstrate that CVB3 infection induces an increased number of double-membrane vesicles, accompanied by an increase of the LC3-II/LC3-I ratio and an accumulation of punctate GFP-LC3-expressing cells, two hallmarks of cellular autophagosome formation. However, protein expression analysis of p62, a marker for autophagy-mediated protein degradation, showed no apparent changes after CVB3 infection. These results suggest that CVB3 infection triggers autophagosome formation without promoting protein degradation by the lysosome. We further examined the role of the autophagosome in CVB3 replication. We demonstrated that inhibition of autophagosome formation by 3-methyladenine or small interfering RNAs targeting the genes critical for autophagosome formation (ATG7, Beclin-1, and VPS34 genes) significantly reduced viral replication. Conversely, induction of autophagy by rapamycin or nutrient deprivation resulted in increased viral replication. Finally, we examined the role of autophagosome-lysosome fusion in viral replication. We showed that blockage of the fusion by gene silencing of the lysosomal protein LAMP2 significantly promoted viral replication. Taken together, our results suggest that the host's autophagy machinery is activated during CVB3 infection to enhance the efficiency of viral replication.
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Shen, Yan, Wei Xu, Yi-Wei Chu, Ying Wang, Quan-Sheng Liu, and Si-Dong Xiong. "Coxsackievirus Group B Type 3 Infection Upregulates Expression of Monocyte Chemoattractant Protein 1 in Cardiac Myocytes, Which Leads to Enhanced Migration of Mononuclear Cells in Viral Myocarditis." Journal of Virology 78, no. 22 (November 15, 2004): 12548–56. http://dx.doi.org/10.1128/jvi.78.22.12548-12556.2004.
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ABSTRACT Coxsackievirus group B type 3 (CVB3) is an important cause of viral myocarditis. The infiltration of mononuclear cells into the myocardial tissue is one of the key events in viral myocarditis. Immediately after CVB3 infects the heart, the expression of chemokine(s) by infected myocardial cells may be the first trigger for inflammatory infiltration and immune response. However, it is unknown whether CVB3 can induce the chemokine expression in cardiac myocytes. Monocyte chemoattractant protein 1 (MCP-1) is a potent chemokine that stimulates the migration of mononuclear cells. The objective of the present study was to investigate the effect of CVB3 infection on MCP-1 expression in murine cardiac myocytes and the role of MCP-1 in migration of mononuclear cells in viral myocarditis. Our results showed that the expression of MCP-1 was significantly increased in cardiac myocytes after wild-type CVB3 infection in a time- and dose-dependent manner, which resulted in enhanced migration of mononuclear cells in mice with viral myocarditis. The migration of mononuclear cells was partially abolished by antibodies specific for MCP-1 in vivo and in vitro. Administration of anti-MCP-1 antibody prevented infiltration of mononuclear cells bearing the MCP-1 receptor CCR2 in mice with viral myocarditis. Infection by UV-irradiated CVB3 induced rapid and transient expression of MCP-1 in cardiac myocytes. In conclusion, our results indicate that CVB3 infection stimulates the expression of MCP-1 in myocardial cells, which subsequently leads to migration of mononuclear cells in viral myocarditis.
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Wang, Meng-Jie, Chun-Hua Yang, Yue Jin, Chang-Biao Wan, Wei-He Qian, Fei Xing, Xiang Li, and Yuan-Yuan Liu. "Baicalin Inhibits Coxsackievirus B3 Replication by Reducing Cellular Lipid Synthesis." American Journal of Chinese Medicine 48, no. 01 (January 2020): 143–60. http://dx.doi.org/10.1142/s0192415x20500081.
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Baicalin is a flavonoid extracted from Scutellariae Radix and shows a variety of biological activities as reducing lipids, diminishing inflammation, and inhibiting bacterial infection. However, there is no report of baicalin against CVB3 infection. In this study, we found that baicalin can reduce viral titer in a dose-dependent manner in vitro at a dose with no direct virucidal effect. Moreover, we revealed that baicalin can also improve survival rate, reduce heart weight/body weight ratio, prevent virus replication, and relieve myocardial inflammation in the acute viral myocarditis mouse model induced by CVB3. Then, in order to explore the mechanism of baicalin inhibiting CVB3 replication, we respectively examined the expression of autophagosome marker LC3-II by Western blot, tested the concentration of free fatty acid (FFA) and cholesterol (CHO) by commercial kits, detected the mRNA levels of fatty acid synthase (Fasn) and acetyl coenzyme a carboxylase (ACC) by RT-PCR, and observed the lipid content of cells by fluorescence staining. The results showed that CVB3 infection increased autophagosome formation and lipid content in HeLa cells, but these changes were significantly blocked by baicalin. Finally, in order to confirm that baicalin inhibits viral replication and reduces autophagosome formation by reducing cellular lipids, we added exogenous palmitate to cell culture supernatants to promote intracellular lipid synthesis and found that palmitate did not alter LC3-II and CVB3/VP1 expression in HeLa cells with or without CVB3 infection. Interestingly, palmitate can reverse the inhibitory effect of baicalin on autophagosome formation and viral replication. In conclusion, our results indicated that lipids play an important role in CVB3 replication, and the effect of baicalin against CVB3 was associated with its ability to reduce cellular lipid synthesis to limit autophagosome formation.
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Han, Tiesuo, Wenqi He, Deguang Song, Kui Zhao, Chenchen Wu, Feng Gao, Huijun Lu, et al. "Experimental SSM-CVB3 infection in macaques." Experimental and Molecular Pathology 92, no. 1 (February 2012): 131–39. http://dx.doi.org/10.1016/j.yexmp.2011.10.008.
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Jagdeo, Julienne M., Antoine Dufour, Gabriel Fung, Honglin Luo, Oded Kleifeld, Christopher M. Overall, and Eric Jan. "Heterogeneous Nuclear Ribonucleoprotein M Facilitates Enterovirus Infection." Journal of Virology 89, no. 14 (April 29, 2015): 7064–78. http://dx.doi.org/10.1128/jvi.02977-14.
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ABSTRACTPicornavirus infection involves a dynamic interplay of host and viral protein interactions that modulates cellular processes to facilitate virus infection and evade host antiviral defenses. Here, using a proteomics-based approach known as TAILS to identify protease-generated neo-N-terminal peptides, we identify a novel target of the poliovirus 3C proteinase, the heterogeneous nuclear ribonucleoprotein M (hnRNP M), a nucleocytoplasmic shuttling RNA-binding protein that is primarily known for its role in pre-mRNA splicing. hnRNP M is cleavedin vitroby poliovirus and coxsackievirus B3 (CVB3) 3C proteinases and is targeted in poliovirus- and CVB3-infected HeLa cells and in the hearts of CVB3-infected mice. hnRNP M relocalizes from the nucleus to the cytoplasm during poliovirus infection. Finally, depletion of hnRNP M using small interfering RNA knockdown approaches decreases poliovirus and CVB3 infections in HeLa cells and does not affect poliovirus internal ribosome entry site translation and viral RNA stability. We propose that cleavage of and subverting the function of hnRNP M is a general strategy utilized by picornaviruses to facilitate viral infection.IMPORTANCEEnteroviruses, a member of the picornavirus family, are RNA viruses that cause a range of diseases, including respiratory ailments, dilated cardiomyopathy, and paralysis. Although enteroviruses have been studied for several decades, the molecular basis of infection and the pathogenic mechanisms leading to disease are still poorly understood. Here, we identify hnRNP M as a novel target of a viral proteinase. We demonstrate that the virus subverts the function of hnRNP M and redirects it to a step in the viral life cycle. We propose that cleavage of hnRNP M is a general strategy that picornaviruses use to facilitate infection.
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Park, Soo Jin, Uram Jin, and Sang Myun Park. "Interaction between coxsackievirus B3 infection and α-synuclein in models of Parkinson’s disease." PLOS Pathogens 17, no. 10 (October 25, 2021): e1010018. http://dx.doi.org/10.1371/journal.ppat.1010018.
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Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. PD is pathologically characterized by the death of midbrain dopaminergic neurons and the accumulation of intracellular protein inclusions called Lewy bodies or Lewy neurites. The major component of Lewy bodies is α-synuclein (α-syn). Prion-like propagation of α-syn has emerged as a novel mechanism in the progression of PD. This mechanism has been investigated to reveal factors that initiate Lewy pathology with the aim of preventing further progression of PD. Here, we demonstrate that coxsackievirus B3 (CVB3) infection can induce α-syn-associated inclusion body formation in neurons which might act as a trigger for PD. The inclusion bodies contained clustered organelles, including damaged mitochondria with α-syn fibrils. α-Syn overexpression accelerated inclusion body formation and induced more concentric inclusion bodies. In CVB3-infected mice brains, α-syn aggregates were observed in the cell body of midbrain neurons. Additionally, α-syn overexpression favored CVB3 replication and related cytotoxicity. α-Syn transgenic mice had a low survival rate, enhanced CVB3 replication, and exhibited neuronal cell death, including that of dopaminergic neurons in the substantia nigra. These results may be attributed to distinct autophagy-related pathways engaged by CVB3 and α-syn. This study elucidated the mechanism of Lewy body formation and the pathogenesis of PD associated with CVB3 infection.
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Carson, Steven D., Kyung-Soo Kim, Samuel J. Pirruccello, Steven Tracy, and Nora M. Chapman. "Endogenous low-level expression of the coxsackievirus and adenovirus receptor enables coxsackievirus B3 infection of RD cells." Journal of General Virology 88, no. 11 (November 1, 2007): 3031–38. http://dx.doi.org/10.1099/vir.0.82710-0.
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Cells in which the appropriate viral receptor cannot be detected may paradoxically act as a host to the virus. For example, RD cells are often considered to be non-permissive for infection with coxsackievirus and adenovirus receptor (CAR)-dependent group B coxsackieviruses (CVB), insofar as inoculated cell monolayers show little or no cytopathic effect (CPE) and immunohistological assays for CAR have been consistently negative. Supernatants recovered from RD cells exposed to CVB, however, contained more virus than was added in the initial inoculum, indicating that productive virus replication occurred in the monolayer. When infected with a recombinant CVB type 3 (CVB3) chimeric strain expressing S-Tag within the viral polyprotein, 4–11 % of RD cells expressed S-Tag over 48 h. CAR mRNA was detected in RD cells by RT-PCR, and CAR protein was detected on Western blots of RD lysates; both were detected at much lower levels than in HeLa cells. Receptor blockade by an anti-CAR antibody confirmed that CVB3 infection of RD cells was mediated by CAR. These results show that some RD cells in the culture population express CAR and can thereby be infected by CVB, which explains the replication of CAR-dependent CVB in cell types that show little or no CPE and in which CAR has not previously been detected. Cells within cultures of cell types that have been considered non-permissive may express receptor transiently, leading to persistent replication of virus within the cultured population.
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Firpo, Mason R., Natalie J. LoMascolo, Marine J. Petit, Priya S. Shah, and Bryan C. Mounce. "Polyamines and eIF5A hypusination facilitate SREBP2 synthesis and cholesterol production leading to enhanced enterovirus attachment and infection." PLOS Pathogens 19, no. 4 (April 18, 2023): e1011317. http://dx.doi.org/10.1371/journal.ppat.1011317.
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Metabolism is key to cellular processes that underlie the ability of a virus to productively infect. Polyamines are small metabolites vital for many host cell processes including proliferation, transcription, and translation. Polyamine depletion also inhibits virus infection via diverse mechanisms, including inhibiting polymerase activity and viral translation. We showed that Coxsackievirus B3 (CVB3) attachment requires polyamines; however, the mechanism was unknown. Here, we report polyamines’ involvement in translation, through a process called hypusination, promotes expression of cholesterol synthesis genes by supporting SREBP2 synthesis, the master transcriptional regulator of cholesterol synthesis genes. Measuring bulk transcription, we find polyamines support expression of cholesterol synthesis genes, regulated by SREBP2. Thus, polyamine depletion inhibits CVB3 by depleting cellular cholesterol. Exogenous cholesterol rescues CVB3 attachment, and mutant CVB3 resistant to polyamine depletion exhibits resistance to cholesterol perturbation. This study provides a novel link between polyamine and cholesterol homeostasis, a mechanism through which polyamines impact CVB3 infection.
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Wang, Yanqi, Zhirong Sun, Hongkai Zhang, Yahui Song, Yi Wang, Wei Xu, and Min Li. "CVB3 Inhibits NLRP3 Inflammasome Activation by Suppressing NF-κB Pathway and ROS Production in LPS-Induced Macrophages." Viruses 15, no. 5 (April 28, 2023): 1078. http://dx.doi.org/10.3390/v15051078.
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Inflammasomes are cytosolic sensors of pathogens. Their activation can lead to the induction of caspase-1-mediated inflammatory responses and the release of several proinflammatory cytokines, including IL-1β. There is a complex relationship between viral infection and the nucleotide-binding oligomerization domain-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome. The activation of the NLRP3 inflammasome is essential for antiviral immunity, while excessive NLRP3 inflammasome activation may lead to excessive inflammation and pathological damage. Meanwhile, viruses have evolved strategies to suppress the activation of inflammasome signaling pathways, thus escaping immune responses. In this study, we investigated the inhibitory effect of coxsackievirus B3 (CVB3), a positive single-strand RNA virus, on the activation of the NLRP3 inflammasome in macrophages. CVB3-infected mice had significantly lower production of IL-1β and a lower level of NLRP3 in the small intestine after LPS stimulation. Furthermore, we found that CVB3 infection inhibited NLRP3 inflammasome activation and IL-1β production in macrophages by suppressing the NF-κB signaling pathway and ROS production. Additionally, CVB3 infection increased the susceptibility of mice to Escherichia coli infection by decreasing IL-1β production. Collectively, our study revealed a novel mechanism of NLRP3 inflammasome activation by suppressing the NF-κB pathway and ROS production in LPS-induced macrophages. Our findings may provide new ideas for antiviral treatment and drug development for CVB3 infection.
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Xiong, Hai-Rong, Yuan-Ying Shen, Li Lu, Wei Hou, Fan Luo, Hong Xiao, and Zhan-Qiu Yang. "The Inhibitory Effect of Rheum palmatum Against Coxsackievirus B3in Vitro and in Vivo." American Journal of Chinese Medicine 40, no. 04 (January 2012): 801–12. http://dx.doi.org/10.1142/s0192415x12500607.
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Coxsackievirus B3(CVB3) infection is the major cause of viral myocarditis, as well as dilated cardiomypathy. Rhubarb is one of the oldest and best-known traditional Chinese medicines. We initiated this study to determine the antiviral effect of an ethanol extract from the roots and rhizoma of Rheum palmatum (R. palmatum, one of the Chinese Rhubarbs), against CVB3 in tissue culture cells and in a mouse model. The ethanol extract from R. palmatum showed significant inhibitory activity against CVB3 on HEp-2 cells when added after infection, with IC50 of 4 μg/ml, TI of 10. The medicated mouse serum still contained the pharmaceutical compound 24 h after intraperitoneal injection, and exhibited an antiviral effect on CVB3-infected cells, especially in the 0.3 and 0.5 g/kg/day treatment groups. Furthermore, the CVB3-infected mice were treated with the extract solution with dosages of 0.3 g/kg/day beginning 24 h post-CVB3 exposures. The ethanol extract treated mice showed alleviated clinical signs, better survival rate, prolonged MTD and decreased viral titers compared to the virus control group. Our results indicate that the ethanol extract from R. palmatum has the anti-CVB3 activity in vitro and in vivo and thus provides a re-evaluation of this old remedy with a broad therapeutic potential.
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Kemball, Christopher C., Stephanie Harkins, and J. Lindsay Whitton. "Enumeration and Functional Evaluation of Virus-Specific CD4+ and CD8+ T Cells in Lymphoid and Peripheral Sites of Coxsackievirus B3 Infection." Journal of Virology 82, no. 9 (February 27, 2008): 4331–42. http://dx.doi.org/10.1128/jvi.02639-07.
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ABSTRACT Previous studies have suggested that coxsackievirus B (CVB) activates CD8+ T cells in vivo, but the extent of this activation and the antigen specificity of the CD8+ T cells remain uncertain. Furthermore, CVB-induced CD4+ T-cell responses have not been carefully investigated. Herein, we evaluate CD8+ and CD4+ T-cell responses both in a secondary lymphoid organ (spleen) and in peripheral tissues (heart and pancreas), using a recombinant CVB3 (rCVB3.6) that encodes well-characterized CD8+ and CD4+ T-cell epitopes. Despite reaching high levels in vivo, rCVB3.6 failed to trigger a marked expansion of CD8+ or CD4+ T cells, and T-cell activation was surprisingly limited. Furthermore, epitope-specific effector functions could not be detected using highly sensitive in vivo and ex vivo assays. Moreover, major histocompatibility complex (MHC) class I tetramer analysis indicated that our inability to detect CVB3-specific CD8+ T-cell responses could not be explained by the cells being dysfunctional. In contrast to naïve T cells, epitope-specific memory CD8+ and CD4+ T cells proliferated markedly, indicating that both of the rCVB3.6-encoded epitopes were presented by their respective MHC molecules in vivo. These data are consistent with the observation that several CVB3 proteins can limit the presentation of viral epitopes on the surface of infected cells and suggest that the level of MHC/peptide complex is sufficient to trigger memory but not naïve T cells. Finally, our findings have implications for the biological significance of cross-priming, a process thought by some to be important for the induction of antiviral CD8+ T-cell responses.
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Feuer, Ralph, Ignacio Mena, Robb Pagarigan, Mark K. Slifka, and J. Lindsay Whitton. "Cell Cycle Status Affects Coxsackievirus Replication, Persistence, and Reactivation In Vitro." Journal of Virology 76, no. 9 (May 1, 2002): 4430–40. http://dx.doi.org/10.1128/jvi.76.9.4430-4440.2002.
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ABSTRACT Enteroviral persistence has been implicated in the pathogenesis of several chronic human diseases, including dilated cardiomyopathy, insulin-dependent diabetes mellitus, and chronic inflammatory myopathy. However, these viruses are considered highly cytolytic, and it is unclear what mechanisms might permit their long-term survival. Here, we describe the generation of a recombinant coxsackievirus B3 (CVB3) expressing the enhanced green fluorescent protein (eGFP), which we used to mark and track infected cells in vitro. Following exposure of quiescent tissue culture cells to either wild-type CVB3 or eGFP-CVB3, virus production was very limited but increased dramatically after cells were permitted to divide. Studies with cell cycle inhibitors revealed that cells arrested at the G1 or G1/S phase could express high levels of viral polyprotein and produced abundant infectious virus. In contrast, both protein expression and virus yield were markedly reduced in quiescent cells (i.e., cells in G0) and in cells blocked at the G2/M phase. Following infection with eGFP-CVB3, quiescent cells retained viral RNA for several days in the absence of infectious virus production. Furthermore, RNA extracted from nonproductive quiescent cells was infectious when transfected into dividing cells, indicating that CVB3 appears to be capable of establishing a latent infection in G0 cells, at least in tissue culture. Finally, wounding of infected quiescent cells resulted in viral protein expression limited to cells in and adjacent to the lesion. We suggest that (i) cell cycle status determines the distribution of CVB3 during acute infection and (ii) the persistence of CVB3 in vivo may rely on infection of quiescent (G0) cells incapable of supporting viral replication; a subsequent change in the cell cycle status may lead to virus reactivation, triggering chronic viral and/or immune-mediated pathology in the host.
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Blum, Samuel I., Ashley R. Burg, Yi-Guang Chen, and Hubert M. Tse. "MDA5 expression impacts immune cell activation during T1D development." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 61.03. http://dx.doi.org/10.4049/jimmunol.206.supp.61.03.
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Abstract Coxsackievirus B3 (CVB3) infection has been associated with triggering Type 1 diabetes (T1D), potentially due to direct β-cell damage and bystander activation of autoreactive T cells. CVB3-infection of Non-Obese Diabetic (NOD) mice accelerates T1D onset, in part due to melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses. However, the role of MDA5 on immune cells during T1D remains unclear. By using mice that contain an in-frame deletion within the helicase 1 domain of MDA5 (ΔHel1) or lack MDA5 expression (KO), we can test the hypothesis that reduced MDA5 expression impairs IFN-α/β synthesis, immune cell activation, and T1D onset. NOD and KO mice develop T1D equally, but ΔHel1 mice exhibit delayed spontaneous and CVB3-accelerated T1D. During spontaneous T1D, 12-week-old ΔHel1 mice had a significant reduction in TNF+ F4/80+ macrophages (MΦ) (1.6-fold), perforin+ CD8+ T cells (13.1-fold), and IFNγ+ CD4+ T cells (6.1-fold), compared to NOD and KO mice. ΔHel1 mice had a significant reduction in pancreatic IFN-α (2.2-fold) and IFN-β (3.1-fold) levels compared to NOD mice following CVB3-infection. CVB3-infected ΔHel1 mice had a significant decrease in pancreatic TNF+ F4/80+ MΦ (2-fold) compared to NOD and KO mice. However, ΔHel1 and KO mice had reduced pancreatic perforin+ CD8+ T cells (2.5-fold) and IFNγ+ CD4+ T cells (1.8-fold) compared to NOD mice following CVB3 infection. The ΔHel1 mutation decreased basal and CVB3-responsive MΦ and T cells within the pancreata thereby delaying T1D onset. Yet, loss of MDA5 expression failed to delay T1D indicating MDA5-dependant responses may be required to prevent T1D. Future studies will determine if T1D onset is dictated by MDA5 dsRNA binding and/or ATPase activity.
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Gao, Guang, Jingchun Zhang, Xiaoning Si, Jerry Wong, Caroline Cheung, Bruce McManus, and Honglin Luo. "Proteasome inhibition attenuates coxsackievirus-induced myocardial damage in mice." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 1 (July 2008): H401—H408. http://dx.doi.org/10.1152/ajpheart.00292.2008.
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Coxsackievirus B3 (CVB3) is one of the most prevalent pathogens of viral myocarditis, which may persist chronically and progress to dilated cardiomyopathy. We previously demonstrated a critical role of the ubiquitin-proteasome system (UPS) in the regulation of coxsackievirus replication in mouse cardiomyocytes. In the present study, we extend our interest to an in vivo animal model to examine the regulation and role of the UPS in CVB3-induced murine myocarditis. Male myocarditis-susceptible A/J mice at age 4–5 wk were randomized to four groups: sham infection + vehicle ( n = 10), sham infection + proteasome inhibitor ( n = 10), virus + vehicle ( n = 20), and virus + proteasome inhibitor ( n = 20). Proteasome inhibitor was administered subcutaneously once a day for 3 days. Mice were killed on day 9 after infection, and infected hearts were harvested for Western blot analysis, plaque assay, immunostaining, and histological examination. We showed that CVB3 infection led to an accumulation of ubiquitin conjugates at 9 days after infection. Protein levels of ubiquitin-activating enzyme E1A/E1B, ubiquitin-conjugating enzyme UBCH7, as well as deubiquitinating enzyme UCHL1 were markedly increased in CVB3-infected mice compared with sham infection. However, there was no significant alteration in proteasome activities at 9 days after infection. Immunohistochemical staining revealed that increased expression of E1A/E1B was mainly localized to virus-damaged cells. Finally, we showed that application of a proteasome inhibitor significantly reduced CVB3-induced myocardial damage. This observation reveals a novel mechanism of coxsackieviral pathogenesis, and suggests that the UPS may be an attractive therapeutic target against coxsackievirus-induced myocarditis.
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Bhakat, Soumendranath. "Effect of T68A/N126Y mutations on the conformational and ligand binding landscape of Coxsackievirus B3 3C protease." Molecular BioSystems 11, no. 8 (2015): 2303–11. http://dx.doi.org/10.1039/c5mb00262a.
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3C protease of Coxsackievirus B3 (CVB3) plays an essential role in the viral replication cycle, and therefore, emerged as an attractive therapeutic target for the treatment of human diseases caused by CVB3 infection.
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Esfandiarei, Mitra, Honglin Luo, Bobby Yanagawa, Agripina Suarez, Darya Dabiri, Jianchang Zhang, and Bruce M. McManus. "Protein Kinase B/Akt Regulates Coxsackievirus B3 Replication through a Mechanism Which Is Not Caspase Dependent." Journal of Virology 78, no. 8 (April 15, 2004): 4289–98. http://dx.doi.org/10.1128/jvi.78.8.4289-4298.2004.
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ABSTRACT The role of signaling pathways including the mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K) during viral infection has gained much recent attention. Our laboratory reported on an important regulatory role for extracellular signal-regulated kinases (ERK1/2), subfamily members of the MAPKs, during coxsackievirus B3 (CVB3) infection. However, the role of the PI3K pathway in CVB3 infection has not been well characterized. CVB3 is the most common known viral infectant of heart muscle that directly injures and kills infected cardiac myocytes during the myocarditic process. In the present study, we investigated the role of protein kinase B (PKB) (also known as Akt), a general downstream mediator of survival signals through the PI3K cascade, in regulating CVB3 replication and virus-induced apoptosis in a well-established HeLa cell model. We have demonstrated that CVB3 infection leads to phosphorylation of PKB/Akt on both Ser-473 and Thr-308 residues through a PI3K-dependent mechanism. Transfection of HeLa cells with a dominant negative mutant of Akt1 or pretreatment of wild-type HeLa cells with the specific PI3K inhibitor LY294002 significantly suppresses viral RNA expression, as reflected in diminished viral capsid protein expression and viral release. Dominant negative Akt1 and LY294002 also increase apoptosis in infected cells, which can be reversed by addition of the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk). Interestingly, blocking of apoptosis by zVAD.fmk does not reverse the viral RNA translation blockade, indicating that the inhibitory effect of dominant negative Akt1 on viral protein expression is not caspase dependent. In addition, we showed that the attachment of virus to its receptor-coreceptor complex is not sufficient for PKB/Akt activation and that postentry viral replication is required for Akt phosphorylation. Taken together, these data illustrate a new and imperative role for Akt in CVB3 infection in HeLa cells and show that the PI3K/Akt signaling is beneficial to CVB3 replication.
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Wang, Maowei, Yan Yue, Chunsheng Dong, Xiaoyun Li, Wei Xu, and Sidong Xiong. "Mucosal Immunization with High-Mobility Group Box 1 in Chitosan Enhances DNA Vaccine-Induced Protection against Coxsackievirus B3-Induced Myocarditis." Clinical and Vaccine Immunology 20, no. 11 (September 11, 2013): 1743–51. http://dx.doi.org/10.1128/cvi.00466-13.
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ABSTRACTCoxsackievirus B3 (CVB3), a small single-stranded RNA virus, belongs to thePicornaviridaefamily. Its infection is the most common cause of myocarditis, with no vaccine available. Gastrointestinal mucosa is the major entry port for CVB3; therefore, the induction of local immunity in mucosal tissues may help control initial viral infections and alleviate subsequent myocardial injury. Here we evaluated the ability of high-mobility group box 1 (HMGB1) encapsulated in chitosan particles to enhance the mucosal immune responses induced by the CVB3-specific mucosal DNA vaccine chitosan-pVP1. Mice were intranasally coimmunized with 4 doses of chitosan-pHMGB1 and chitosan-pVP1 plasmids, at 2-week intervals, and were challenged with CVB3 4 weeks after the last immunization. Compared with chitosan-pVP1 immunization alone, coimmunization with chitosan-pHMGB1 significantly (P< 0.05) enhanced CVB3-specific fecal secretory IgA levels and promoted mucosal T cell immune responses. In accordance, reduced severity of myocarditis was observed in coimmunized mice, as evidenced by significantly (P< 0.05) reduced viral loads, decreased myocardial injury, and increased survival rates. Flow cytometric analysis indicated that HMGB1 enhanced dendritic cell (DC) recruitment to mesenteric lymph nodes and promoted DC maturation, which might partly account for its mucosal adjuvant effect. This strategy may represent a promising approach to candidate vaccines against CVB3-induced myocarditis.