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Roark, Hunter K., Jennifer A. Jenks, Sallie R. Permar i Mark R. Schleiss. "Animal Models of Congenital Cytomegalovirus Transmission: Implications for Vaccine Development". Journal of Infectious Diseases 221, Supplement_1 (5.03.2020): S60—S73. http://dx.doi.org/10.1093/infdis/jiz484.
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Abstract Although cytomegaloviruses (CMVs) are species-specific, the study of nonhuman CMVs in animal models can help to inform and direct research aimed at developing a human CMV (HCMV) vaccine. Because the driving force behind the development of HCMV vaccines is to prevent congenital infection, the animal model in question must be one in which vertical transmission of virus occurs to the fetus. Fortunately, two such animal models—the rhesus macaque CMV and guinea pig CMV—are characterized by congenital infection. Hence, each model can be evaluated in “proof-of-concept” studies of preconception vaccination aimed at blocking transplacental transmission. This review focuses on similarities and differences in the respective model systems, and it discusses key insights from each model germane to the study of HCMV vaccines.
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Moulden, Jerome, Cathy Yea Won Sung, Ilija Brizic, Stipan Jonjic i William Britt. "Murine Models of Central Nervous System Disease following Congenital Human Cytomegalovirus Infections". Pathogens 10, nr 8 (21.08.2021): 1062. http://dx.doi.org/10.3390/pathogens10081062.
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Human cytomegalovirus infection of the developing fetus is a leading cause of neurodevelopmental disorders in infants and children, leading to long-term neurological sequela in a significant number of infected children. Current understanding of the neuropathogenesis of this intrauterine infection is limited because of the complexity of this infection, which includes maternal immunological responses that are overlaid on virus replication in the CNS during neurodevelopment. Furthermore, available data from human cases are observational, and tissues from autopsy studies have been derived from only the most severe infections. Animal models of this human infection are also limited by the strict species specificity of cytomegaloviruses. However, informative models including non-human primates and small animal models have been developed. These include several different murine models of congenital HCMV infection for the study of CMV neuropathogenesis. Although individual murine models do not completely recapitulate all aspects of the human infection, each model has provided significant information that has extended current understanding of the neuropathogenesis of this human infection. This review will compare and contrast different murine models in the context of available information from human studies of CNS disease following congenital HCMV infections.
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Kern, Earl R., Deborah J. Bidanset, Caroll B. Hartline, Zhaohua Yan, Jiri Zemlicka i Debra C. Quenelle. "Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections". Antimicrobial Agents and Chemotherapy 48, nr 12 (grudzień 2004): 4745–53. http://dx.doi.org/10.1128/aac.48.12.4745-4753.2004.
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ABSTRACT We reported previously that purine 2-(hydroxymethyl)methylenecyclopropane analogs have good activity against cytomegalovirus infection. A second-generation analog, (Z)-9-{[2,2-bis-(hydroxymethyl)cyclopropylidene]methyl}guanine (ZSM-I-62, cyclopropavir [CPV]), has particularly good activity against murine and human cytomegaloviruses (MCMV and HCMV) in vitro. To determine the oral activity of this compound in vivo, BALB/c or severe combined immunodeficient (SCID) mice infected with MCMV and two models using SCID mice implanted with human fetal tissue and subsequently infected with HCMV were used. In MCMV-infected normal mice, CPV at 10 mg/kg of body weight was highly effective in preventing mortality when administered at 24, 48, or 72 h post-viral inoculation and reduced titers of virus in tissues of SCID mice by 2 to 5 log10. In one HCMV model, human fetal retinal tissue was implanted into the anterior chamber of the mouse eye and inoculated with the Toledo strain of HCMV, and in the second, human fetal thymus and liver tissues were implanted under the kidney capsule of mice and then inoculated with HCMV. In general, replication of HCMV in both types of implant tissue increased from 7 through 21 to 28 days and then gradually decreased to undetectable levels by 8 weeks postinfection. Oral treatment with 45 or 15 mg of CPV/kg initiated 24 h after infection was highly effective in reducing replication to undetectable levels in both models and was generally more effective than ganciclovir. These data indicate that the methylenecyclopropane analog, CPV, was highly efficacious in these four animal models and should be evaluated for use in HCMV infections in humans.
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Taher, Husam, Eisa Mahyari, Craig Kreklywich, Luke S. Uebelhoer, Matthew R. McArdle, Matilda J. Moström, Amruta Bhusari i in. "In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome". PLOS Pathogens 16, nr 11 (24.11.2020): e1008666. http://dx.doi.org/10.1371/journal.ppat.1008666.
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Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the only available RhCMV clone that permits genetic modifications is based on the 68–1 strain which has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptations. As a result, 68–1 displays reduced viremia in RhCMV-naïve animals and limited shedding compared to non-clonal, low passage isolates. To overcome this limitation, we used sequence information from primary RhCMV isolates to construct a full-length (FL) RhCMV by repairing all mutations affecting open reading frames (ORFs) in the 68–1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naïve RM with the reconstituted virus resulted in significant viremia in the blood similar to primary isolates of RhCMV and furthermore led to high viral genome copy numbers in many tissues at day 14 post infection. In contrast, viral dissemination was greatly reduced upon deletion of genes also lacking in 68–1. Transcriptome analysis of infected tissues further revealed that chemokine-like genes deleted in 68–1 are among the most highly expressed viral transcripts both in vitro and in vivo consistent with an important immunomodulatory function of the respective proteins. We conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while being amenable to genetic modifications through BAC recombineering techniques.
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Farrell, Helen. "Animal models of human cytomegalovirus congenital infection". Microbiology Australia 36, nr 4 (2015): 196. http://dx.doi.org/10.1071/ma15068.
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Human cytomegalovirus (HCMV) infection is highly species-specific, which means that it is unable to productively infect laboratory animals. Despite this caveat, studies of animal CMV counterparts in their natural hosts have revealed significant correlations with observed neuropathological effects of congenital HCMV infection and have improved our understanding of host responses to vaccination. The biological relatedness between human and animal CMVs has been confirmed by phylogenetic analyses; the conservation of ‘core' genes that are essential for virus replication as well as genes that contribute similar mechanisms for virus persistence in their respective host species. The common animal models of HCMV congenital infection include Rhesus CMV (RhCMV), guinea-pig CMV (GPCMV) and mouse CMV (MCMV). Whilst animal models of CMV do not fully recapitulate HCMV infection, they each offer specific advantages in understanding HCMV congenital/perinatal infection (summarised in Table 1).
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McGregor, Alistair, i K. Yeon Choi. "Cytomegalovirus antivirals and development of improved animal models". Expert Opinion on Drug Metabolism & Toxicology 7, nr 10 (wrzesień 2011): 1245–65. http://dx.doi.org/10.1517/17425255.2011.613824.
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Imperiale, Michael J., i Mengxi Jiang. "What DNA Viral Genomic Rearrangements Tell Us about Persistence". Journal of Virology 89, nr 4 (3.12.2014): 1948–50. http://dx.doi.org/10.1128/jvi.01227-14.
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Understanding the life cycle and pathogenesis of animal viruses requires that we have systems in which the viruses can replicate and cause disease. For the latter, we rely upon animal models or information that we can obtain from studying natural infections of humans and other animals. For the former, however, we are largely dependent on the availability of cell culture systems in which viruses can be propagated to investigate the molecular mechanisms of viral replication. For many years, it was assumed that replication in culture provided an accurate description of the life cycle of the organism. In this Gem, we will discuss two viruses, polyomavirus and cytomegalovirus, in which cell culture systems have accidentally provided unique potential insights into viral replication and persistence in their hosts.
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Tsutsui, Yoshihiro. "Developmental disorders of the mouse brain induced by murine cytomegalovirus: Animal models for congenital cytomegalovirus infection". Pathology International 45, nr 2 (luty 1995): 91–102. http://dx.doi.org/10.1111/j.1440-1827.1995.tb03428.x.
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Kaul, Artur, Uwe Schönmann i Stefan Pöhlmann. "Seroprevalence of viral infections in captive rhesus and cynomolgus macaques". Primate Biology 6, nr 1 (26.03.2019): 1–6. http://dx.doi.org/10.5194/pb-6-1-2019.
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Abstract. Macaques serve as important animal models for biomedical research. Viral infection of macaques can compromise animal health as well as the results of biomedical research, and infected animals constitute an occupational health risk. Therefore, monitoring macaque colonies for viral infection is an important task. We used a commercial chip-based assay to analyze sera of 231 macaques for the presence of antibody responses against nine animal and human viruses. We report high seroprevalence of cytomegalovirus (CMV), lymphocryptovirus (LCV), rhesus rhadinovirus (RRV) and simian foamy virus (SFV) antibodies in all age groups. In contrast, antibodies against simian retrovirus type D (SRV/D) and simian T cell leukemia virus (STLV) were detected only in 5 % and 10 % of animals, respectively, and were only found in adult or aged animals. Moreover, none of the animals had antibodies against herpes B virus (BV), in keeping with the results of in-house tests previously used for screening. Finally, an increased seroprevalence of measles virus antibodies in animals with extensive exposure to multiple humans for extended periods of time was observed. However, most of these animals were obtained from external sources, and a lack of information on the measles antibody status of the animals at the time of arrival precluded drawing reliable conclusions from the data. In sum, we show, that in the colony studied, CMV, LCV, RRV and SFV infection was ubiquitous and likely acquired early in life while SRV/D and STLV infection was rare and likely acquired during adulthood.
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Kanai, Kyosuke, Souichi Yamada, Yumiko Yamamoto, Yoshiko Fukui, Ichiro Kurane i Naoki Inoue. "Re-evaluation of the genome sequence of guinea pig cytomegalovirus". Journal of General Virology 92, nr 5 (1.05.2011): 1005–20. http://dx.doi.org/10.1099/vir.0.027789-0.
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Congenital infection by human cytomegalovirus (HCMV) is a major cause of birth defects and developmental abnormalities. Since guinea pig cytomegalovirus (GPCMV) crosses the placenta and causes infection in utero, GPCMV models are useful for studies of the mechanisms of transplacental transmission. During our characterization of a genomic locus required for GPCMV dissemination in animals, we found that the nucleotide sequence in and around the nearby immediate–early genes in our lineage of GPCMV strain 22122 [designated GPCMV (ATCC-P5)] showed clear differences from that reported previously for the same strain [designated GPCMV (UMN)] passaged extensively in vitro. Since in vitro passaging of HCMV is known to result in genetic alterations, especially in the UL128–UL131A locus, and loss of growth ability in particular cell types, in this study we determined the complete genome sequence of GPCMV (ATCC-P5), which grows efficiently in animals. A total of 359 differences were identified between the genome sequences of GPCMV (UMN) and GPCMV (ATCC-P5), and these resulted in structural differences in 29 protein-encoding regions. In addition, some genes predicted from our analysis but not from GPCMV (UMN) are well conserved among cytomegaloviruses. An additional 18 passages of GPCMV (ATCC-P5) in vitro generated no further marked alterations in these genes or in the locus corresponding to the HCMV UL128–UL131A. Our analyses indicate that the published sequence of GPCMV (UMN) contains a substantial number of sequencing errors and, possibly, some mutations resulting from a long history of passaging in vitro. Our re-evaluation of the genetic content of GPCMV will provide a solid foundation for future studies.
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Koffron, Alan J., Mary Hummel, Bruce K. Patterson, Shixian Yan, Dixon B. Kaufman, Jonathan P. Fryer, Frank P. Stuart i Michael I. Abecassis. "Cellular Localization of Latent Murine Cytomegalovirus". Journal of Virology 72, nr 1 (1.01.1998): 95–103. http://dx.doi.org/10.1128/jvi.72.1.95-103.1998.
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ABSTRACT Herpesviruses typically establish latent infection in their hosts. The cell(s) responsible for harboring latent virus, in most cases, is not known. Using immunofluorescence and PCR-in situ hybridization (PISH), a technique which combines the sensitivity of PCR with the localization and specificity of in situ hybridization, we provide the first direct evidence that endothelial cells are a major site of murine cytomegalovirus (MCMV) DNA in latently infected animals. These findings are consistent with existing knowledge of the biological behavior of CMV, in particular the transmission of latent CMV by solid organ and bone marrow transplantation, in both human and animal models. In addition, we have localized MCMV DNA in the lung alveolar macrophage and in bone marrow cells. Our findings confirm that bone marrow-derived hematopoietic cells are a site of CMV latency and further suggest that bone marrow may be a reservoir of infected progeny capable of migrating into the circulation and establishing latency in various tissues. These findings provide clearly needed insight into the site of latent infection which is central to an understanding of the mechanisms of reactivation.
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Schleiss, Mark R. "Animal models of congenital cytomegalovirus infection: an overview of progress in the characterization of guinea pig cytomegalovirus (GPCMV)". Journal of Clinical Virology 25 (sierpień 2002): 37–49. http://dx.doi.org/10.1016/s1386-6532(02)00100-2.
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Kern, Earl R., Caroll B. Hartline, Rachel J. Rybak, John C. Drach, Leroy B. Townsend, Karen K. Biron i Deborah J. Bidanset. "Activities of Benzimidazole d- and l-Ribonucleosides in Animal Models of Cytomegalovirus Infections". Antimicrobial Agents and Chemotherapy 48, nr 5 (maj 2004): 1749–55. http://dx.doi.org/10.1128/aac.48.5.1749-1755.2004.
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ABSTRACT Since human cytomegalovirus (HCMV) does not infect or replicate in nonhuman cells and tissues, there are few animal models currently available for evaluation of antiviral therapies for these infections. In the present studies, we utilized two different models in which severe combined immunodeficient (SCID) mice were implanted with human fetal tissue that was subsequently infected with HCMV. In one model, human fetal retinal tissue was implanted into the anterior chamber of the SCID mouse eye, and in the second, human fetal thymus and liver (thy/liv) tissues were implanted under the kidney capsule. After the implants were established, they were infected with 2,000 to 9,000 PFU of HCMV. To determine the efficacy of three benzimidazole nucleosides, 2-bromo-5,6-dichloro-(1-β-d-ribofuranosyl)benzimidazole (BDCRB), GW275175X (175X), and GW257406X (1263W94, maribavir [MBV]) treatment was initiated 24 h after infection of the implants and continued for 28 days. Treatment consisted of either placebo, 25 mg of ganciclovir (GCV)/kg of body weight administered intraperitoneally (i.p.) twice daily, 33 or 100 mg of BDCRB/kg administered i.p. twice daily, or 75 mg of either MBV or 175X/kg administered orally twice daily. GCV was effective in both models, inhibiting HCMV infection by 5- to 3,000-fold. In the retinal tissue model, MBV and BDCRB reduced HCMV replication about fourfold through 21 days postinfection compared with results for the vehicle control. In the thy/liv tissue model, all three benzimidazole nucleosides were effective in inhibiting HCMV replication by approximately 30- to 3,000-fold in comparison to the vehicle control. These data indicate that the benzimidazole nucleosides were efficacious in these animal models and suggest that this class of compounds should be active against the various HCMV infections that occur in the immunocompromised host.
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Kern, Earl R. "Pivotal role of animal models in the development of new therapies for cytomegalovirus infections". Antiviral Research 71, nr 2-3 (wrzesień 2006): 164–71. http://dx.doi.org/10.1016/j.antiviral.2006.05.018.
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Weber, Olaf, Jürgen Reefschläger, Helga Rübsamen-Waigmann, Siegfried Raddatz, Matthias Hesseling i Dieter Häbich. "A Novel Peptide Aldehyde with Activity against Human Cytomegalovirus in Two Different in Vivo Models". Antiviral Chemistry and Chemotherapy 11, nr 1 (luty 2000): 51–59. http://dx.doi.org/10.1177/095632020001100105.
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Novel peptide aldehydes (PAs) were identified as potent inhibitors of human cytomegalovirus (HCMV) in vitro. Although these compounds were highly effective against HCMV, they did not exhibit any activity against murine cytomegalovirus (MCMV). The purpose of this study was to test the antiviral activity of PA 8 as a representative of this novel class of inhibitors against HCMV in vivo. Because of the strict species specificity of HCMV we had to use two artificial animal models. In the first model, HCMV-infected human cells were entrapped into agarose plugs and transplanted into mice. In the second model, SCID mice were transplanted with human tissues that were subsequently infected with a clinical isolate of HCMV. In these two models the antiviral activity of PA 8 was clearly demonstrated, ganciclovir only being slightly superior in its in vivo antiviral activity.
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Barry, P. A., K. M. Lockridge, S. Salamat, S. P. Tinling, Y. Yue, S. S. Zhou, S. M. Gospe, W. J. Britt i A. F. Tarantal. "Nonhuman Primate Models of Intrauterine Cytomegalovirus Infection". ILAR Journal 47, nr 1 (1.01.2006): 49–64. http://dx.doi.org/10.1093/ilar.47.1.49.
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Hitchcock, M. J. M., H. S. Jaffe, J. C. Martin i R. J. Stagg. "Cidofovir, a New Agent with Potent Anti-Herpesvirus Activity". Antiviral Chemistry and Chemotherapy 7, nr 3 (czerwiec 1996): 115–27. http://dx.doi.org/10.1177/095632029600700301.
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Cidofovir is a potent, broad spectrum antiviral agent with activity in vitro and in vivo against cytomegalovirus and other members of the herpesvirus family, as well as certain other DNA viruses. After uptake into cells it is converted enzymatically to cidofovir diphosphate, a structural analogue of deoxycytidine triphosphate, which selectively inhibits viral DNA polymerases relative to host cell polymerases. Cross-resistance to cidofovir is not usually seen with human cytomegalovirus isolates that are foscarnet-resistant, or isolates that are ganciclovir-resistant due to a deficiency in ganciclovir phosphorylation. Cross-resistance is seen, however, with isolates that are ganciclovir resistant due to polymerase mutations. A prolonged elimination phase seen in vivo, correlates with a long intracellular half-life seen in vitro and allows for efficacy in animal models of virus infection with infrequent dosing or prophylaxis. Clinical studies of intravenous cidofovir in cytomegalovirus retinitis in patients with AIDS are claimed to show delay of retinitis progression with maintenance doses given once every 2 weeks.
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Podlech, Jürgen, Rares Pintea, Kai A. Kropp, Annette Fink, Niels A. W. Lemmermann, Katja C. Erlach, Elena Isern, Ana Angulo, Peter Ghazal i Matthias J. Reddehase. "Enhancerless Cytomegalovirus Is Capable of Establishing a Low-Level Maintenance Infection in Severely Immunodeficient Host Tissues but Fails in Exponential Growth". Journal of Virology 84, nr 12 (7.04.2010): 6254–61. http://dx.doi.org/10.1128/jvi.00419-10.
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ABSTRACT Major immediate-early transcriptional enhancers are genetic control elements that act, through docking with host transcription factors, as a decisive regulatory unit for efficient initiation of the productive virus cycle. Animal models are required for studying the function of enhancers paradigmatically in host organs. Here, we have sought to quantitatively assess the establishment, maintenance, and level of in vivo growth of enhancerless mutants of murine cytomegalovirus in comparison with those of an enhancer-bearing counterpart in models of the immunocompromised or immunologically immature host. Evidence is presented showing that enhancerless viruses are capable of forming restricted foci of infection but fail to grow exponentially.
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Lundstrom, Kenneth. "Self-Replicating RNA Viruses for RNA Therapeutics". Molecules 23, nr 12 (13.12.2018): 3310. http://dx.doi.org/10.3390/molecules23123310.
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Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.
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Barouch, Dan H., Zhi-yong Yang, Wing-pui Kong, Birgit Korioth-Schmitz, Shawn M. Sumida, Diana M. Truitt, Michael G. Kishko i in. "A Human T-Cell Leukemia Virus Type 1 Regulatory Element Enhances the Immunogenicity of Human Immunodeficiency Virus Type 1 DNA Vaccines in Mice and Nonhuman Primates". Journal of Virology 79, nr 14 (lipiec 2005): 8828–34. http://dx.doi.org/10.1128/jvi.79.14.8828-8834.2005.
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ABSTRACT Plasmid DNA vaccines elicit potent and protective immune responses in numerous small-animal models of infectious diseases. However, their immunogenicity in primates appears less potent. Here we investigate a novel approach that optimizes regulatory elements in the plasmid backbone to improve the immunogenicity of DNA vaccines. Among various regions analyzed, we found that the addition of a regulatory sequence from the R region of the long terminal repeat from human T-cell leukemia virus type 1 (HTLV-1) to the cytomegalovirus (CMV) enhancer/promoter increased transgene expression 5- to 10-fold and improved cellular immune responses to human immunodeficiency virus type 1 (HIV-1) antigens. In cynomolgus monkeys, DNA vaccines containing the CMV enhancer/promoter with the HTLV-1 R region (CMV/R) induced markedly higher cellular immune responses to HIV-1 Env from clades A, B, and C and to HIV-1 Gag-Pol-Nef compared with the parental DNA vaccines. These data demonstrate that optimization of specific regulatory elements can substantially improve the immunogenicity of DNA vaccines encoding multiple antigens in small animals and in nonhuman primates. This strategy could therefore be explored as a potential method to enhance DNA vaccine immunogenicity in humans.
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Jackson, Joseph, i Tim Sparer. "There Is Always Another Way! Cytomegalovirus’ Multifaceted Dissemination Schemes". Viruses 10, nr 7 (20.07.2018): 383. http://dx.doi.org/10.3390/v10070383.
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Human cytomegalovirus (HCMV) is a β-herpes virus that is a significant pathogen within immune compromised populations. HCMV morbidity is induced through viral dissemination and inflammation. Typically, viral dissemination is thought to follow Fenner’s hypothesis where virus replicates at the site of infection, followed by replication in the draining lymph nodes, and eventually replicating within blood filtering organs. Although CMVs somewhat follow Fenner’s hypothesis, they deviate from it by spreading primarily through innate immune cells as opposed to cell-free virus. Also, in vivo CMVs infect new cells via cell-to-cell spread and disseminate directly to secondary organs through novel mechanisms. We review the historic and recent literature pointing to CMV’s direct dissemination to secondary organs and the genes that it has evolved for increasing its ability to disseminate. We also highlight aspects of CMV infection for studying viral dissemination when using in vivo animal models.
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Quenelle, Debra C., Deborah J. Collins, Latisha R. Pettway, Caroll B. Hartline, James R. Beadle, W. Brad Wan, Karl Y. Hostetler i Earl R. Kern. "Effect of oral treatment with (S)-HPMPA, HDP-(S)-HPMPA or ODE-(S)-HPMPA on replication of murine cytomegalovirus (MCMV) or human cytomegalovirus (HCMV) in animal models". Antiviral Research 79, nr 2 (sierpień 2008): 133–35. http://dx.doi.org/10.1016/j.antiviral.2008.01.155.
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Crawford, Lindsey B., Rebecca Tempel, Daniel N. Streblow, Andrew D. Yurochko, Felicia D. Goodrum, Jay A. Nelson i Patrizia Caposio. "Human Cytomegalovirus Infection Suppresses CD34+ Progenitor Cell Engraftment in Humanized Mice". Microorganisms 8, nr 4 (6.04.2020): 525. http://dx.doi.org/10.3390/microorganisms8040525.
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Human cytomegalovirus (HCMV) infection is a serious complication in hematopoietic stem cell transplant (HSCT) recipients due to virus-induced myelosuppression and impairment of stem cell engraftment. Despite the clear clinical link between myelosuppression and HCMV infection, little is known about the mechanism(s) by which the virus inhibits normal hematopoiesis because of the strict species specificity and the lack of surrogate animal models. In this study, we developed a novel humanized mouse model system that recapitulates the HCMV-mediated engraftment failure after hematopoietic cell transplantation. We observed significant alterations in the hematopoietic populations in peripheral lymphoid tissues following engraftment of a subset of HCMV+ CD34+ hematopoietic progenitor cells (HPCs) within the transplant, suggesting that a small proportion of HCMV-infected CD34+ HPCs can profoundly affect HPC differentiation in the bone marrow microenvironment. This model will be instrumental to gain insight into the fundamental mechanisms of HCMV myelosuppression after HSCT and provides a platform to assess novel treatment strategies.
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Santos Rocha, Clarissa, Lauren A. Hirao, Mariana G. Weber, Gema Méndez-Lagares, W. L. William Chang, Guochun Jiang, Jesse D. Deere i in. "Subclinical Cytomegalovirus Infection Is Associated with Altered Host Immunity, Gut Microbiota, and Vaccine Responses". Journal of Virology 92, nr 13 (18.04.2018): e00167-18. http://dx.doi.org/10.1128/jvi.00167-18.
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ABSTRACTSubclinical viral infections (SVI), including cytomegalovirus (CMV), are highly prevalent in humans, resulting in lifelong persistence. However, the impact of SVI on the interplay between the host immunity and gut microbiota in the context of environmental exposures is not well defined. We utilized the preclinical nonhuman primate (NHP) model consisting of SVI-free (specific-pathogen-free [SPF]) rhesus macaques and compared them to the animals with SVI (non-SPF) acquired through natural exposure and investigated the impact of SVI on immune cell distribution and function, as well as on gut microbiota. These changes were examined in animals housed in the outdoor environment compared to the controlled indoor environment. We report that SVI are associated with altered immune cell subsets and gut microbiota composition in animals housed in the outdoor environment. Non-SPF animals harbored a higher proportion of potential butyrate-producingFirmicutesand higher numbers of lymphocytes, effector T cells, and cytokine-producing T cells. Surprisingly, these differences diminished following their transfer to the controlled indoor environment, suggesting that non-SPFs had increased responsiveness to environmental exposures. An experimental infection of indoor SPF animals with CMV resulted in an increased abundance of butyrate-producing bacteria, validating that CMV enhanced colonization of butyrate-producing commensals. Finally, non-SPF animals displayed lower antibody responses to influenza vaccination compared to SPF animals. Our data show that subclinical CMV infection heightens host immunity and gut microbiota changes in response to environmental exposures. This may contribute to the heterogeneity in host immune response to vaccines and environmental stimuli at the population level.IMPORTANCEHumans harbor several latent viruses that modulate host immunity and commensal microbiota, thus introducing heterogeneity in their responses to pathogens, vaccines, and environmental exposures. Most of our understanding of the effect of CMV on the immune system is based on studies of children acquiring CMV or of immunocompromised humans with acute or reactivated CMV infection or in ageing individuals. The experimental mouse models are genetically inbred and are completely adapted to the indoor laboratory environment. In contrast, nonhuman primates are genetically outbred and are raised in the outdoor environment. Our study is the first to report the impact of long-term subclinical CMV infection on host immunity and gut microbiota, which is evident only in the outdoor environment but not in the indoor environment. The significance of this study is in highlighting the impact of SVI on enhancing host immune susceptibility to environmental exposures and immune heterogeneity.
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Britt, William. "Maternal Immunity and the Natural History of Congenital Human Cytomegalovirus Infection". Viruses 10, nr 8 (3.08.2018): 405. http://dx.doi.org/10.3390/v10080405.
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Congenital human cytomegalovirus (HCMV) is the most common viral infection of the developing fetus, and a significant cause of neurodevelopmental abnormalities in infants and children. Congenital HCMV infections account for an estimated 25% of all cases of hearing loss in the US. It has long been argued that maternal adaptive immune responses to HCMV can modify both the likelihood of intrauterine transmission of HCMV, and the severity of fetal infection and risk of long term sequelae in infected infants. Over the last two decades, multiple studies have challenged this paradigm, including findings that have demonstrated that the vast majority of infants with congenital HCMV infections in most populations are born to women with established immunity prior to conception. Furthermore, the incidence of clinically apparent congenital HCMV infection in infants born to immune and non-immune pregnant women appears to be similar. These findings from natural history studies have important implications for the design, development, and testing of prophylactic vaccines and biologics for this perinatal infection. This brief overview will provide a discussion of existing data from human natural history studies and animal models of congenital HCMV infections that have described the role of maternal immunity in the natural history of this perinatal infection.
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Liu, Jian, Dabbu Kumar Jaijyan, Qiyi Tang i Hua Zhu. "Promising Cytomegalovirus-Based Vaccine Vector Induces Robust CD8+ T-Cell Response". International Journal of Molecular Sciences 20, nr 18 (10.09.2019): 4457. http://dx.doi.org/10.3390/ijms20184457.
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Vaccination has had great success in combating diseases, especially infectious diseases. However, traditional vaccination strategies are ineffective for several life-threatening diseases, including acquired immunodeficiency syndrome (AIDS), tuberculosis, malaria, and cancer. Viral vaccine vectors represent a promising strategy because they can efficiently deliver foreign genes and enhance antigen presentation in vivo. However, several limitations, including pre-existing immunity and packaging capacity, block the application of viral vectors. Cytomegalovirus (CMV) has been demonstrated as a new type of viral vector with additional advantages. CMV could systematically elicit and maintain high frequencies of effector memory T cells through the “memory inflation” mechanism. Studies have shown that CMV can be genetically modified to induce distinct patterns of CD8+ T-cell responses, while some unconventional CD8+ T-cell responses are rarely induced through conventional vaccine strategies. CMV has been used as a vaccine vector to deliver many disease-specific antigens, and the efficacy of these vaccines was tested in different animal models. Promising results demonstrated that the robust and unconventional T-cell responses elicited by the CMV-based vaccine vector are essential to control these diseases. These accumulated data and evidence strongly suggest that a CMV-based vaccine vector represents a promising approach to develop novel prophylactic and therapeutic vaccines against some epidemic pathogens and tumors.
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La Rosa, Corinna, Zhongde Wang, John C. Brewer, Simon F. Lacey, Maria C. Villacres, Rahul Sharan, Radhika Krishnan i in. "Preclinical development of an adjuvant-free peptide vaccine with activity against CMV pp65 in HLA transgenic mice". Blood 100, nr 10 (15.11.2002): 3681–89. http://dx.doi.org/10.1182/blood-2002-03-0926.
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Epitope vaccines have shown promise for inducing cellular immune responses in animal models of infectious disease. In cases where cellular immunity was augmented, peptide vaccines composed of covalently linked minimal cytotoxic T-lymphocyte (CTL) and T-helper (TH) epitopes generally showed the most efficacy. To address a clinical vaccine strategy for cytomegalovirus (CMV) in the context of HCT (hematopoietic cell transplantation), we observed that linking the synthetically derived pan-DR epitope peptide (PADRE) or one of several tetanus TH epitopes to the immunodominant human leukocyte antigen (HLA) A*0201–restricted CTL epitope from CMV-pp65 to create a fusion peptide caused robust cytotoxic cellular immune responses in HLA A*0201/Kbtransgenic mice. Significantly, the fusion peptides are immunogenic when administered in saline solution by either subcutaneous or intranasal routes. CpG-containing single-stranded DNA (ss-oligodeoxynucleotide [ODN]) added to the fusion peptides dramatically up-regulated immune recognition by either route. Notably, target cells that either expressed full-length pp65 protein from vaccinia viruses or were sensitized with the CTL epitope encoded in the vaccine were recognized by splenic effectors from immunized animals. Visualization of murine peptide–specific CTL by flow cytometry was accomplished using an HLA A*0201 tetramer complexed with the pp65495-503 CTL epitope. TH-CTL epitope fusion peptides in combination with CpG ss-ODN represent a new strategy for parenteral or mucosal delivery of vaccines in a safe and effective manner that has applicability for control or prophylaxis of infectious disease, especially in situations such as vaccination of donors or recipients of HCT, where highly inflammatory adjuvants are not desired.
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Njue, Annete, Carolyn Coyne, Andrea V. Margulis, Dai Wang, Morgan A. Marks, Kevin Russell, Rituparna Das i Anushua Sinha. "The Role of Congenital Cytomegalovirus Infection in Adverse Birth Outcomes: A Review of the Potential Mechanisms". Viruses 13, nr 1 (24.12.2020): 20. http://dx.doi.org/10.3390/v13010020.
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Human cytomegalovirus (CMV) is a major cause of nonhereditary adverse birth outcomes, including hearing and visual loss, neurologic deficits, and intrauterine growth retardation (IUGR), and may contribute to outcomes such as stillbirth and preterm delivery. However, the mechanisms by which CMV could cause adverse birth outcomes are not fully understood. This study reviewed proposed mechanisms underlying the role of CMV in stillbirth, preterm birth, and IUGR. Targeted literature searches were performed in PubMed and Embase to identify relevant articles. Several potential mechanisms were identified from in vitro studies in which laboratory-adapted and low-passage strains of CMV and various human placental models were used. Potential mechanisms identified included impairment of trophoblast progenitor stem cell differentiation and function, impairment of extravillous trophoblast invasiveness, dysregulation of Wnt signaling pathways in cytotrophoblasts, tumor necrosis factor-α mediated apoptosis of trophoblasts, CMV-induced cytokine changes in the placenta, inhibition of indoleamine 2,3-dioxygenase activity, and downregulation of trophoblast class I major histocompatibility complex molecules. Inherent challenges for the field remain in the identification of suitable in vivo animal models. Nonetheless, we believe that our review provides useful insights into the mechanisms by which CMV impairs placental development and function and how these changes could result in adverse birth outcomes.
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Xu, Yanqun, Iftekhar Mahmood, Lilin Zhong, Pei Zhang i Evi B. Struble. "Passive Immunoprophylaxis for the Protection of the Mother and Her Baby: Insights from In Vivo Models of Antibody Transport". Journal of Immunology Research 2017 (2017): 1–8. http://dx.doi.org/10.1155/2017/7373196.
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Pregnant women are at high risk for infection by pathogens. Vertical transmission of infectious agents, such as Zika, hepatitis B, and cytomegalovirus during pregnancy, remains a public health problem, associated with dire outcomes for the neonate. Thus, a safe prophylactic and therapeutic approach for protecting the mother and the neonate from infections remains a high priority. Our work is focused on better understanding the safety and efficacy determinants of IgG antibody preparations when used during pregnancy to benefit the mother and her baby. Using pregnant guinea pigs, we demonstrated that biodistribution of administered IgG to the fetus increases with gestation and results in lower maternal and higher fetal antibody concentrations as pregnancy progresses. Data suggests that partition of antibody immunotherapy to the fetal compartment may contribute to a lower maternal exposure (as measured by the AUC) and a shorter mean residence time of the IgG therapeutic at the end of pregnancy compared to nonpregnant age-matched controls, irrespective of the administered dose. Our studies provide insights on the importance of selecting an efficacious dose in pregnancy that takes into account IgG biodistribution to the fetus. The use of appropriate animal models of placental transfer and infectious disease during pregnancy would facilitate pharmacokinetic modeling to derive a starting dose in clinical trials.
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Luganini, Anna, Patrizia Caposio, Santo Landolfo i Giorgio Gribaudo. "Phosphorothioate-Modified Oligodeoxynucleotides Inhibit Human Cytomegalovirus Replication by Blocking Virus Entry". Antimicrobial Agents and Chemotherapy 52, nr 3 (7.01.2008): 1111–20. http://dx.doi.org/10.1128/aac.00987-07.
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ABSTRACT Studies in animal models have provided evidence that Toll-like receptor 9 (TLR9) agonists, such as synthetic oligodeoxynucleotides (ODNs) that contain immunostimulatory deoxycytidyl-deoxyguanosine (CpG) motifs (CpG ODNs), protect against a wide range of viral pathogens. This antiviral activity has been suggested to be indirect and secondary to CpG-induced cytokines and inflammatory responses triggered through TLR9 activation. However, few studies have addressed the potential of CpG ODNs as direct antiviral agents. Here, we report on the ability of some CpG ODNs to directly suppress, almost completely, human cytomegalovirus (HCMV) replication in both primary fibroblasts and endothelial cells. Murine CMV replication was inhibited as well, whereas no inhibition was observed for herpes simplex virus type 1, adenovirus, or vesicular stomatitis virus. The antiviral activity of these ODNs was significantly reduced when they were added after virus adsorption, indicating that their action may be primarily targeted to the very early phases of the HCMV cycle. In fact, the B-class prototype CpG ODN 2006 effectively prevented the nuclear localization of pp65 and input viral DNA, which suggests that it inhibits HCMV entry. Moreover, a CpG 2006 control, ODN 2137 without CpG motifs, also showed a potent inhibitory activity on the HCMV entry phase, indicating that the anticytomegaloviral activity is independent of the CpG motif. In contrast, a phosphodiester version of CpG 2006 showed reduced antiviral activity, indicating that the inhibitory activity is dependent on the phosphorothioate backbone of the ODN. These results suggest that this yet-unrecognized activity of CpG ODNs may be of interest in the development of novel anticytomegaloviral molecules.
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Reddehase, Matthias, i Niels Lemmermann. "Mouse Model of Cytomegalovirus Disease and Immunotherapy in the Immunocompromised Host: Predictions for Medical Translation that Survived the “Test of Time”". Viruses 10, nr 12 (6.12.2018): 693. http://dx.doi.org/10.3390/v10120693.
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Human Cytomegalovirus (hCMV), which is the prototype member of the β-subfamily of the herpesvirus family, is a pathogen of high clinical relevance in recipients of hematopoietic cell transplantation (HCT). hCMV causes multiple-organ disease and interstitial pneumonia in particular upon infection during the immunocompromised period before hematopoietic reconstitution restores antiviral immunity. Clinical investigation of pathomechanisms and of strategies for an immune intervention aimed at restoring antiviral immunity earlier than by hematopoietic reconstitution are limited in patients to observational studies mainly because of ethical issues including the imperative medical indication for chemotherapy with antivirals. Aimed experimental studies into mechanisms, thus, require animal models that match the human disease as close as possible. Any model for hCMV disease is, however, constrained by the strict host-species specificity of CMVs that prevents the study of hCMV in any animal model including non-human primates. During eons of co-speciation, CMVs each have evolved a set of “private genes” in adaptation to their specific mammalian host including genes that have no homolog in the CMV virus species of any other host species. With a focus on the mouse model of CD8 T cell-based immunotherapy of CMV disease after experimental HCT and infection with murine CMV (mCMV), we review data in support of the phenomenon of “biological convergence” in virus-host adaptation. This includes shared fundamental principles of immune control and immune evasion, which allows us to at least make reasoned predictions from the animal model as an experimental “proof of concept.” The aim of a model primarily is to define questions to be addressed by clinical investigation for verification, falsification, or modification and the results can then give feedback to refine the experimental model for research from “bedside to bench”.
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Schleiss, M. R. "Nonprimate Models of Congenital Cytomegalovirus (CMV) Infection: Gaining Insight into Pathogenesis and Prevention of Disease in Newborns". ILAR Journal 47, nr 1 (1.01.2006): 65–72. http://dx.doi.org/10.1093/ilar.47.1.65.
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Peoples, M., M. Golding, C. Long i M. Westhusin. "141 DEVELOPMENT OF rLENTIVIRAL VECTORS FOR MALE GERMLINE-SPECIFIC Cre RECOMBINASE EXPRESSION IN LIVESTOCK". Reproduction, Fertility and Development 24, nr 1 (2012): 183. http://dx.doi.org/10.1071/rdv24n1ab141.
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Transgenic livestock have been used as biomedical models and have the potential to increase production characteristics. Unfortunately, some of the tools used to confirm genetic modification (transgenesis) are unacceptable in terms of public image. One key component is a fluorescent marker confirming foreign gene insert. The fluorescent protein benefits the researchers producing and selecting transgenic animals but is not required for the enhancement of the animal. Removal of the fluorescent marker can be accomplished by employing the Cre-lox recombination system. By using this system one can produce male genetically modified animals that express the enhanced trait in addition to the fluorescent marker, but their sperm only contain the portion of the transgene that represents the enhanced production trait. As a result, offspring derived from these animals exhibit the desired production trait but not the fluorescent marker. The goal of this research was to develop rlentiviral vectors that use the gamete-specific promoter stimulated by retinoic acid 8 (Stra8) to drive expression of Cre recombinase. The base rlentiviral vector we chose to use was pLB. It is ideal for this research because it has a U6 promoter to drive expression of a short hairpin RNA for an enhanced production trait, as well as Lox P sites flanking a cytomegalovirus-green fluorescent protein (CMV-GFP) expression cassette. Initially we identified and PCR amplified a 400-bp mouse Stra8 promoter and a 1.5-kb promoter region of the pig. The Stra8 promoters were integrated into the pLB vector directly upstream of the green fluorescent protein (GFP). These intermediate vectors should have germline-specific expression of GFP and are the first vectors using a pig Stra8 promoter. Next, we PCR amplified and inserted the coding sequence for Cre recombinase into these vectors for germline-specific Cre expression resulting in the first pig Stra8-Cre expression vector. The Lox P sites of this vector are flanking the GFP expression cassette as well as the Str8-Cre expression cassette. To confirm the functionality of the Cre-lox recombination system, the pLB vectors were transfected into human embryonic kindey 293T cells and fluorescence was measured. After Day 2, a Cre expression plasmid was transfected and 3 days post-Cre transfection, fluorescence was measured again. A decrease in fluorescence and GFP positive cell numbers was observed, thus confirming the functionality of the Cre-lox recombination event for these vectors. These vectors will be used to produce transgenic animals by lentiviral transgenesis. Our laboratory has been successful in using this method to produce transgenic livestock. The transgenic animals will be analysed to confirm male germ-cell-specific expression of Cre as well as removal of the GFP fluorescence. If successful, these will be the first transgenic animals using a pig Stra8 promoter for Cre expression for a novel single rlentiviral vector Cre-lox recombination system.
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Macedo-da-Silva, Janaina, Claudio Romero Farias Marinho, Giuseppe Palmisano i Livia Rosa-Fernandes. "Lights and Shadows of TORCH Infection Proteomics". Genes 11, nr 8 (5.08.2020): 894. http://dx.doi.org/10.3390/genes11080894.
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Congenital abnormalities cause serious fetal consequences. The term TORCH is used to designate the most common perinatal infections, where: (T) refers to toxoplasmosis, (O) means “others” and includes syphilis, varicella-zoster, parvovirus B19, zika virus (ZIKV), and malaria among others, (R) refers to rubella, (C) relates to cytomegalovirus infection, and (H) to herpes simplex virus infections. Among the main abnormalities identified in neonates exposed to congenital infections are central nervous system (CNS) damage, microcephaly, hearing loss, and ophthalmological impairment, all requiring regular follow-up to monitor its progression. Protein changes such as mutations, post-translational modifications, abundance, structure, and function may indicate a pathological condition before the onset of the first symptoms, allowing early diagnosis and understanding of a particular disease or infection. The term “proteomics” is defined as the science that studies the proteome, which consists of the total protein content of a cell, tissue or organism in a given space and time, including post-translational modifications (PTMs) and interactions between proteins. Currently, quantitative bottom-up proteomic strategies allow rapid and high throughput characterization of complex biological mixtures. Investigating proteome modulation during host–pathogen interaction helps in elucidating the mechanisms of infection and in predicting disease progression. This “molecular battle” between host and pathogen is a key to identify drug targets and diagnostic markers. Here, we conducted a survey on proteomic techniques applied to congenital diseases classified in the terminology “TORCH”, including toxoplasmosis, ZIKV, malaria, syphilis, human immunodeficiency virus (HIV), herpes simplex virus (HSV) and human cytomegalovirus (HCVM). We have highlighted proteins and/or protein complexes actively involved in the infection. Most of the proteomic studies reported have been performed in cell line models, and the evaluation of tissues (brain, muscle, and placenta) and biofluids (plasma, serum and urine) in animal models is still underexplored. Moreover, there are a plethora of studies focusing on the pathogen or the host without considering the triad mother-fetus-pathogen as a dynamic and interconnected system.
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Tessanne, K., T. Stroud, C. Long, G. Hannon, S. Sadeghieh, E. Hwang, S. Chen, I. Polejaeva i M. Westhusin. "308 DEVELOPMENT OF TRANSGENIC LIVESTOCK WITH REDUCED MYOSTATIN EXPRESSION USING RNA INTERFERENCE". Reproduction, Fertility and Development 21, nr 1 (2009): 251. http://dx.doi.org/10.1071/rdv21n1ab308.
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RNA interference (RNAi) is a means of regulating gene expression by targeting mRNA in a sequence-specific manner for degradation or translational inhibition. Short hairpin RNAs (shRNAs) and siRNAs have been extensively employed for manipulating gene expression in a wide range of species. However, the great majority of this work has involved in vitro studies with cells grown in culture. Our goal for this project is to produce transgenic livestock in which myostatin, a negative regulator of muscle growth, has been targeted for silencing by RNAi. In theory, livestock in which myostatin has been silenced should exhibit increased muscle growth and development. To that end, we designed shRNAs to target the bovine myostatin mRNA sequence. The shRNAs were cloned into a lentiviral vector that contains a cytomegalovirus promoter controlling green fluorescent protein and shRNA expression as well as neomycin resistance. Infective lentivirus was made in HEK293T cells through co-transfection of the lentiviral vector, a packaging plasmid, and a plasmid expressing the VSVG pseudotype. Bovine fetal fibroblasts were transduced, selected using Geneticin®, and nuclear transfer was utilized to produce cloned transgenic embryos. There were 186 fusion attempts resulting in 160 fused embryos (fusion rate = 86%). Of these, 54 reached the blastocyst stage (34%) and 10 embryos were transferred into 5 recipient females (2 embryos per recipient). At 40 days, ultrasound revealed 1 confirmed pregnancy. Current plans are to harvest this fetus at 90 days and analyze it for evidence of myostatin knockdown. The production of transgenic animals exhibiting myostatin knockdown through lentiviral-mediated RNAi will demonstrate the utility of RNAi in the study of gene function in large animal models without the need for homologous recombination techniques, which are currently inefficient in species other than mice.
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Kaur, Amitinder, Michael Rosenzweig i R. Paul Johnson. "Immunological memory and acquired immunodeficiency syndrome pathogenesis". Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 355, nr 1395 (29.03.2000): 381–90. http://dx.doi.org/10.1098/rstb.2000.0578.
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Infection with the human immunodeficiency virus results in profound perturbations in immunological memory, ultimately resulting in increased susceptibility to opportunistic infections and acquired immunodeficiency syndrome (AIDS). W e have used rhesus macaques infected with the simian immunodeficiency virus (SIV) as a model to understand better the effects of AIDS virus infection on immunological memory. Acute infection with SIV resulted in significant deficits in CD4 + helper responses to cytomegalovirus (CMV) as well as CMV–specific cytotoxic T–lymphocyte and neutralizing antibody responses. Reactivation of CMV was associated with high levels of SIV replication and suppression of both T–helper and cytotoxic responses to CMV . We have also studied the effects of SIV infection on T–cell turnover in non–human primates. T–cell turnover was evaluated using the nucleoside analogue bromodeoxyuridine (BrdU) in combination with five–colour flow cytometric analysis. T cells in normal animals turned over at relatively rapid rates, with memory cells turning over more quickly than naive cells. In SIV–infected animals, the labelling and elimination rates of both CD4 + and CD8 + BrdU–labelled cells were increased by two– to threefold compared with normal controls. Further analysis of immunological memory in nonhuman primates should offer the opportunity to extend immunological insights from murine models to the pathogenesis and prevention of AIDS.
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Scarpini, Sara, Francesca Morigi, Ludovica Betti, Arianna Dondi, Carlotta Biagi i Marcello Lanari. "Development of a Vaccine against Human Cytomegalovirus: Advances, Barriers, and Implications for the Clinical Practice". Vaccines 9, nr 6 (25.05.2021): 551. http://dx.doi.org/10.3390/vaccines9060551.
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Human cytomegalovirus (hCMV) is one of the most common causes of congenital infection in the post-rubella era, representing a major public health concern. Although most cases are asymptomatic in the neonatal period, congenital CMV (cCMV) disease can result in permanent impairment of cognitive development and represents the leading cause of non-genetic sensorineural hearing loss. Moreover, even if hCMV mostly causes asymptomatic or pauci-symptomatic infections in immunocompetent hosts, it may lead to severe and life-threatening disease in immunocompromised patients. Since immunity reduces the severity of disease, in the last years, the development of an effective and safe hCMV vaccine has been of great interest to pharmacologic researchers. Both hCMV live vaccines—e.g., live-attenuated, chimeric, viral-based—and non-living ones—subunit, RNA-based, virus-like particles, plasmid-based DNA—have been investigated. Encouraging data are emerging from clinical trials, but a hCMV vaccine has not been licensed yet. Major difficulties in the development of a satisfactory vaccine include hCMV’s capacity to evade the immune response, unclear immune correlates for protection, low number of available animal models, and insufficient general awareness. Moreover, there is a need to determine which may be the best target populations for vaccine administration. The aim of the present paper is to examine the status of hCMV vaccines undergoing clinical trials and understand barriers limiting their development.
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Streblow, Daniel N., Craig Kreklywich, Qiang Yin, V. T. De La Melena, Christopher L. Corless, Patricia A. Smith, Christina Brakebill i in. "Cytomegalovirus-Mediated Upregulation of Chemokine Expression Correlates with the Acceleration of Chronic Rejection in Rat Heart Transplants". Journal of Virology 77, nr 3 (1.02.2003): 2182–94. http://dx.doi.org/10.1128/jvi.77.3.2182-2194.2003.
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ABSTRACT Cytomegalovirus (CMV) infections have been shown to dramatically affect solid organ transplant graft survival in both human and animal models. Recently, it was demonstrated that rat CMV (RCMV) infection accelerates the development of transplant vascular sclerosis (TVS) in both rat heart and small bowel graft transplants. However, the mechanisms involved in this process are still unclear. In the present study, we determined the kinetics of RCMV-accelerated TVS in a rat heart transplant model. Acute RCMV infection enhances the development of TVS in rat heart allografts, and this process is initiated between 21 and 24 days posttransplantation. The virus is consistently detected in the heart grafts from day 7 until day 35 posttransplantation but is rarely found at the time of graft rejection (day 45 posttransplantation). Grafts from RCMV-infected recipients had upregulation of chemokine expression compared to uninfected controls, and the timing of this increased expression paralleled that of RCMV-accelerated neointimal formation. In addition, graft vessels from RCMV-infected grafts demonstrate the increased infiltration of T cells and macrophages during periods of highest chemokine expression. These results suggest that CMV-induced acceleration of TVS involves the increased graft vascular infiltration of inflammatory cells through enhanced chemokine expression.
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Puttini, Stefania, Ahmed T. Beggah, Antoine Ouvrard-Pascaud, Christine Legris, Marcel Blot-Chabaud, Nicolette Farman i Frederic Jaisser. "Tetracycline-inducible gene expression in cultured rat renal CD cells and in intact CD from transgenic mice". American Journal of Physiology-Renal Physiology 281, nr 6 (1.12.2001): F1164—F1172. http://dx.doi.org/10.1152/ajprenal.0360.2000.
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First published August 30, 2001; 10.1152/ajprenal.00360.2000.—The renal collecting duct (CD) plays a key role in the control of ion and fluid homeostasis. Several genetic diseases that involve mutations in genes encoding for ion transporters or hormone receptors specifically expressed in CD have been described. Suitable cellular or transgenic animal models expressing such mutated genes in an inducible manner should represent attractive systems for structure-function relationship analyses and the generation of appropriate physiopathological models of related diseases. Our first goal was to develop a CD cell line that allows inducible gene expression using the tetracycline-inducible system (Tet-On). We designed several strategies aimed at the development of a tight and highly inducible system in RCCD1 cells, a rat cortical collecting duct (CCD) cell line exhibiting several properties of the native CCD. Analysis of reporter gene expression demonstrated that the Tet-On system is suitable for inducible gene expression in these cells. In a second step, we have tested whether transgenic Tet-On mice expressing the tetracycline transactivator under the control of the human cytomegalovirus promoter were suitable for inducible gene expression in tubule epithelial cells. The results indicate that, in vivo , the inducible expression of the lacZ reporter gene appeared to be restricted to the CD. This particular strain of transgenic mice may therefore be useful for the expression of genes of interest in an inducible manner in the collecting duct.
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De Clercq, Erik. "Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections". Clinical Microbiology Reviews 16, nr 4 (październik 2003): 569–96. http://dx.doi.org/10.1128/cmr.16.4.569-596.2003.
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SUMMARY The acyclic nucleoside phosphonates HPMPC (cidofovir), PMEA (adefovir), and PMPA (tenofovir) have proved to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections: cidofovir against herpesvirus (herpes simplex virus types 1 and 2 varicella-zoster virus, cytomegalovirus [CMV], Epstein-Barr virus, and human herpesviruses 6, 7, and 8), polyomavirus, papillomavirus, adenovirus, and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus, and orf virus) infections; adefovir against herpesvirus, hepadnavirus (human hepatitis B virus), and retrovirus (human immunodeficiency virus types 1 [HIV-1] and 2 [HIV-2], simian immunodeficiency virus, and feline immunodeficiency virus) infections; and tenofovir against both hepadnavirus and retrovirus infections. Cidofovir (Vistide) has been officially approved for the treatment of CMV retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) has been approved for the treatment of HIV infections (i.e., AIDS), and adefovir dipivoxil (Hepsera) has been approved for the treatment of chronic hepatitis B. Nephrotoxicity is the dose-limiting side effect for cidofovir (Vistide) when used intravenously (5 mg/kg); no toxic side effects have been described for adefovir dipivoxil and tenofovir disoproxil fumarate, at the approved doses (Hepsera at 10 mg orally daily and Viread at 300 mg orally daily).
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Carmeliet, Peter, Jean-Marie Stassen, Ilse Van Vlaenderen, Robert S. Meidell, Désiré Collen i Robert D. Gerard. "Adenovirus-Mediated Transfer of Tissue-Type Plasminogen Activator Augments Thrombolysis in Tissue-Type Plasminogen Activator–Deficient and Plasminogen Activator Inhibitor-1–Overexpressing Mice". Blood 90, nr 4 (15.08.1997): 1527–34. http://dx.doi.org/10.1182/blood.v90.4.1527.
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AbstractImpaired fibrinolysis, resulting from increased plasminogen activator inhibitor-1 (PAI-1) or reduced tissue-type plasminogen activator (t-PA) plasma levels, may predispose the individual to subacute thrombosis in sepsis and inflammation. The objective of these studies was to show that adenovirus-mediated gene transfer could increase systemic plasma t-PA levels and thrombolytic capacity in animal model systems. Recombinant adenovirus vectors were constructed that express either human wild type or PAI-1–resistant t-PA from the cytomegalovirus (CMV) promoter. Both t-PA-deficient (t-PA−/−) and PAI-1–overexpressing transgenic mice were infected by intravenous injection of these viruses. Intravenous injection of recombinant adenovirus resulted in liver gene transfer, t-PA synthesis, and secretion into the plasma. Virus dose, human t-PA antigen, and activity concentrations in plasma and extent of lysis of a 125I-fibrin–labeled pulmonary embolism were all closely correlated. Plasma t-PA antigen and activity were increased approximately 1,000-fold above normal levels. Clot lysis was significantly increased in mice injected with a t-PA–expressing virus, but not in mice injected with saline or an irrelevant adenovirus. Comparable levels of enzyme activity and clot lysis were obtained with wild type and inhibitor-resistant t-PA viruses. Adenovirus-mediated t-PA gene transfer was found to augment clot lysis as early as 4 hours after infection, but expression levels subsided within 7 days. Adenovirus-mediated transfer of a t-PA gene can effectively increase plasma fibrinolytic activity and either restore (in t-PA–deficient mice) or augment (in PAI-1–overexpressing mice) the thrombolytic capacity in simple animal models of defective fibrinolysis.
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Carmeliet, Peter, Jean-Marie Stassen, Ilse Van Vlaenderen, Robert S. Meidell, Désiré Collen i Robert D. Gerard. "Adenovirus-Mediated Transfer of Tissue-Type Plasminogen Activator Augments Thrombolysis in Tissue-Type Plasminogen Activator–Deficient and Plasminogen Activator Inhibitor-1–Overexpressing Mice". Blood 90, nr 4 (15.08.1997): 1527–34. http://dx.doi.org/10.1182/blood.v90.4.1527.1527_1527_1534.
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Impaired fibrinolysis, resulting from increased plasminogen activator inhibitor-1 (PAI-1) or reduced tissue-type plasminogen activator (t-PA) plasma levels, may predispose the individual to subacute thrombosis in sepsis and inflammation. The objective of these studies was to show that adenovirus-mediated gene transfer could increase systemic plasma t-PA levels and thrombolytic capacity in animal model systems. Recombinant adenovirus vectors were constructed that express either human wild type or PAI-1–resistant t-PA from the cytomegalovirus (CMV) promoter. Both t-PA-deficient (t-PA−/−) and PAI-1–overexpressing transgenic mice were infected by intravenous injection of these viruses. Intravenous injection of recombinant adenovirus resulted in liver gene transfer, t-PA synthesis, and secretion into the plasma. Virus dose, human t-PA antigen, and activity concentrations in plasma and extent of lysis of a 125I-fibrin–labeled pulmonary embolism were all closely correlated. Plasma t-PA antigen and activity were increased approximately 1,000-fold above normal levels. Clot lysis was significantly increased in mice injected with a t-PA–expressing virus, but not in mice injected with saline or an irrelevant adenovirus. Comparable levels of enzyme activity and clot lysis were obtained with wild type and inhibitor-resistant t-PA viruses. Adenovirus-mediated t-PA gene transfer was found to augment clot lysis as early as 4 hours after infection, but expression levels subsided within 7 days. Adenovirus-mediated transfer of a t-PA gene can effectively increase plasma fibrinolytic activity and either restore (in t-PA–deficient mice) or augment (in PAI-1–overexpressing mice) the thrombolytic capacity in simple animal models of defective fibrinolysis.
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Wiebusch, Lüder, Anke Neuwirth, Linus Grabenhenrich, Sebastian Voigt i Christian Hagemeier. "Cell Cycle-Independent Expression of Immediate-Early Gene 3 Results in G1 and G2 Arrest in Murine Cytomegalovirus-Infected Cells". Journal of Virology 82, nr 20 (30.07.2008): 10188–98. http://dx.doi.org/10.1128/jvi.01212-08.
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ABSTRACT The infectious cycle of human cytomegalovirus (HCMV) is intricately linked to the host's cell cycle. Viral gene expression can be initiated only in G0/G1 phase. Once expressed, the immediate-early gene product IE2 prevents cellular DNA synthesis, arresting infected cells with a G1 DNA content. This function is required for efficient viral replication in vitro. A prerequisite for addressing its in vivo relevance is the characterization of cell cycle-regulatory activities of CMV species for which animal models have been established. Here, we show that murine CMV (MCMV), like HCMV, has a strong antiproliferative capacity and arrests cells in G1. Unexpectedly, and in contrast to HCMV, MCMV can also block cells that have passed through S phase by arresting them in G2. Moreover, MCMV can also replicate in G2 cells. This is made possible by the cell cycle-independent expression of MCMV immediate-early genes. Transfection experiments show that of several MCMV candidate genes, only immediate-early gene 3 (ie3), the homologue of HCMV IE2, exhibits cell cycle arrest activity. Accordingly, an MCMV ie3 deletion mutant has lost the ability to arrest cells in either G1 or G2. Thus, despite interspecies variations in the cell cycle dependence of viral gene expression, the central theme of HCMV IE2-induced cell cycle arrest is conserved in the murine counterpart, raising the possibility of studying its physiological relevance at the level of the whole organism.
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De Vusser, Katrien, Dries Martens, Evelyne Lerut, Dirk Kuypers, Tim S. Nawrot i Maarten Naesens. "Replicative senescence and arteriosclerosis after kidney transplantation". Nephrology Dialysis Transplantation 35, nr 11 (17.10.2020): 1984–95. http://dx.doi.org/10.1093/ndt/gfaa151.
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Abstract Background Replicative senescence is associated with telomere shortening. In native kidneys, obtained prior to transplantation, we recently described and validated a significant association between shorter intrarenal telomere length and renal arteriosclerosis. After renal transplantation, animal experiments suggested that ischaemia–reperfusion injury, acute rejection episodes and cytomegalovirus disease associate with accelerated renal allograft senescence. The association between post-transplant events and replicative senescence has not yet been evaluated in a human setting. Methods In a cohort of 134 kidney allograft recipients, we performed protocol-specified renal allograft biopsies at 3 months, 1 year, 2 years and 5 years after transplantation (n = 579 biopsies). We used quantitative real-time polymerase chain reaction to measure intrarenal relative average telomere length (T/S ratio). The association between donor and recipient demographic factors, post-transplant clinical/histological events, renal allograft histological evolution by 5 years post-transplant and intrarenal telomere length at 5 years after transplantation was studied using multiple regression models. Results At 5 years after transplantation, shorter intrarenal telomere length was associated with male donor gender, older donor age, donor history of hypertension and donor cardiovascular risk, which confirms the associations observed in native kidneys. Recipient characteristics and post-transplant events like delayed graft function, acute rejection episodes, presence of donor-specific antibodies, cytomegalovirus disease and immunosuppressive regimen did not associate with alterations of intrarenal telomere length at 5 years. Independent of donor age and donor cardiovascular risk, intrarenal arteriosclerosis in protocol biopsies obtained at 5 years after transplantation and progressive arteriosclerosis over time after transplantation associated with shorter telomere length, while this was not the case for other histological lesions. Moreover, telomere attrition augments the association between older donor age and the presence of severe arteriosclerosis. In the group with the oldest donor age and shortest telomere length, there was significantly more severe arteriosclerosis (43%) in protocol biopsies at 5 years after transplantation, compared with other combinations (13–28%) (P = 0.001). Intrarenal arteriosclerosis at 5 years after transplantation did not associate with post-transplant clinical events. Conclusions We demonstrate that intrarenal telomere length at 5 years after transplantation, as a marker for replicative senescence, associates with renal arteriosclerosis and reflects kidney donor characteristics, but not post-transplant events.
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Morrey, John D., Brent E. Korba, James R. Beadle, David L. Wyles i Karl Y. Hostetler. "Alkoxyalkyl Esters of 9-(S)-(3-Hydroxy-2-Phosphonomethoxypropyl) Adenine Are Potent and Selective Inhibitors of Hepatitis B Virus (HBV) Replication In Vitro and in HBV Transgenic Mice In Vivo". Antimicrobial Agents and Chemotherapy 53, nr 7 (27.04.2009): 2865–70. http://dx.doi.org/10.1128/aac.00114-09.
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ABSTRACT Alkoxyalkyl esters of acyclic nucleoside phosphonates have previously been shown to have increased antiviral activity when they are administered orally in animal models of viral diseases, including lethal infections with vaccinia virus, cowpox virus, ectromelia virus, murine cytomegalovirus, and adenovirus. 9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was previously shown to have activity against hepatitis B virus (HBV) in vitro. To assess the effect of alkoxyalkyl esterification of (S)-HPMPA, we prepared the hexadecyloxypropyl (HDP), 15-methyl-hexadecyloxypropyl (15M-HDP), and octadecyloxyethyl (ODE) esters and compared their activities with the activity of adefovir dipivoxil in vitro and in vivo. Alkoxyalkyl esters of (S)-HPMPA were 6 to 20 times more active than unmodified (S)-HPMPA on the basis of their 50% effective concentrations in 2.2.15 cells. The increased antiviral activity appeared to be due in part to the increased uptake and conversion of HDP-(S)-HPMPA to HPMPA diphosphate observed in HepG2 cells in vitro. HDP-(S)-HPMPA retained full activity against HBV mutants resistant to lamivudine (L180M, M204V), but cross-resistance to a mutant resistant to adefovir (N236T) was detected. HDP-(S)-HPMPA is orally bioavailable and provides excellent liver exposure to the drug. Oral treatment of HBV transgenic mice with HDP-(S)-HPMPA, 15M-HDP-(S)-HPMPA, and ODE-(S)-HPMPA for 14 days reduced liver HBV DNA levels by roughly 1.5 log units, a response equivalent to that of adefovir dipivoxil.
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Seldin, David C., Jennifer Ward, Ruiyi Ren, Gianluca Toraldo, Pamela T. SooHoo, Jian Guan, Carl O'Hara i in. "Doxycycline Reduces Fibril Formation in a Transgenic Mouse Model of AL Amyloidosis". Blood 118, nr 21 (18.11.2011): 1837. http://dx.doi.org/10.1182/blood.v118.21.1837.1837.
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Abstract Abstract 1837 AL amyloidosis results from the production and aggregation of an amyloidogenic immunoglobulin (Ig) light chain (LC) by a clonal bone marrow plasma cell dyscrasia. Currently, there are no genetically reproducible animal models of AL amyloidosis. We engineered transgenic mice to express an amyloidogenic human λ6 LC. We used the cytomegalovirus (CMV) promoter to express the LC in multiple tissues and organs, circumventing the disruption of B cell development by premature expression of recombined LC in the B lineage alone. LC were detected in a number of organs including epithelial tissues of the gastrointestinal and genitourinary tracts, and in the serum. The CMV-λ6 transgenic mice developed neurologic dysfunction. By 2 years of age, >80% of the transgenic mice developed Congo-red staining human LC fibrils in the stomach. Transgenic mice were treated with the antibiotic doxycycline orally for 7 months. Of treated mice, 23% had Congophilic deposits, compared with 69% of controls drinking water for the same time period. Treatment of recombinant LC in vitro with doxycycline reduced fibril formation and the drug also caused to disruption of pre-formed fibrils, producing disordered aggregates. Thus, this transgenic model replicates the process of AL amyloidosis in vivo and is useful for testing the anti-fibril potential of orally available agents. Antibiotics such as doxycycline could prove useful in AL as well as in other amyloidoses. Disclosures: No relevant conflicts of interest to declare.
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Bu, Xuan, Yang Zhou, Hua Zhang, Wenjing Qiu, Lu Chen, Hongdi Cao, Li Fang, Ping Wen, Ruoyun Tan i Junwei Yang. "Systemic administration of naked plasmid encoding HGF attenuates puromycin aminonucleoside-induced damage of murine glomerular podocytes". American Journal of Physiology-Renal Physiology 301, nr 4 (październik 2011): F784—F792. http://dx.doi.org/10.1152/ajprenal.00210.2011.
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Podocyte injury is considered to play important roles in the pathogenesis of human glomerular disease. There is accumulating evidence suggesting that hepatocyte growth factor (HGF) elicits preventive activity for glomerular cells in animal models of chronic renal diseases. In this study, we demonstrated that delivery of a naked plasmid vector encoding the human HGF gene into mice by a hydrodynamic-based in vivo gene transfection approach markedly reduced proteinuria and attenuated podocyte injury in a mouse model induced by puromycin aminonucleoside (PAN) injection. Systemic administration by rapid injection via the tail vein of a naked plasmid containing HGF cDNA driven under a cytomegalovirus promoter (pCMV-HGF) produced a remarkable level of human HGF protein in the circulation. Tissue distribution studies suggested that the kidney expressed a high level of the HGF transgene. Meanwhile, compared with tubules and interstitium, a higher level of exogenous HGF protein was detected in the glomeruli. Administration of pCMV-HGF dramatically abated the urine albumin excretion and podocyte injury in PAN nephropathy in mice. Exogenous expression of HGF produced evidently beneficial effects, leading to restoration of Wilms' tumor-1 (WT1) and α-actinin-4 expression and attenuation of ultrastructural damage of the podocytes. In vitro, HGF not only restored WT1 and α-actinin-4 expression but also inhibited albumin leakage of podocytes incubated with PAN in a Transwell culture chamber. These results suggest that HGF might provide a novel strategy for amelioration of podocyte injury.
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Wang, Weijia, Shannon L. Taylor, Stacey A. Leisenfelder, Robert Morton, Jennifer F. Moffat, Sergey Smirnov i Hua Zhu. "Human Cytomegalovirus Genes in the 15-Kilobase Region Are Required for Viral Replication in Implanted Human Tissues in SCID Mice". Journal of Virology 79, nr 4 (15.02.2005): 2115–23. http://dx.doi.org/10.1128/jvi.79.4.2115-2123.2005.
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ABSTRACT Since animal models for studying human cytomegalovirus (HCMV) replication in vivo and pathogenesis are not available, severe combined immunodeficiency mice into which human tissues were implanted (SCID-hu mice) provide an alternative and valuable model for such studies. The HCMV clinical isolates, including those of the Toledo strain, replicate to high titers in human tissue implanted into SCID mice; however, the attenuated AD169 strain has completely lost this ability. The major difference between Toledo and AD169 is a 15-kb segment, encoding 19 open reading frames, which is present in all virulent strains but deleted from attenuated strains. This fact suggests that crucial genes required for HCMV replication in vivo are localized to this region. In this study, the importance of this 15-kb segment for HCMV replication in vivo was determined. First, ToledoBAC virus (produced from a Toledo bacterial artificial chromosome) and AD169 virus were tested for growth in SCID-hu mice. ToledoBAC, like Toledo, grew to high titers in implanted human thymus and liver tissues, while AD169 did not. This outcome showed that the Toledo genome propagated in bacteria (ToledoBAC) retained its virulence. The 15-kb segment was then deleted from ToledoBAC, and the resulting virus, ToledoΔ15kb, was tested for growth in both human foreskin fibroblast (HFF) cells and SCID-hu mice. ToledoΔ15kb had a minor growth defect in HFF but completely failed to replicate in human thymus and liver implants. This failure to grow was rescued when the 15-kb region was inserted back into the ToledoΔ15kb genome. These results directly demonstrated that the genes located in the 15-kb segment are crucial for HCMV replication in vivo.
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Khandaker, G. M., J. Zimbron, G. Lewis i P. B. Jones. "Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies". Psychological Medicine 43, nr 2 (16.04.2012): 239–57. http://dx.doi.org/10.1017/s0033291712000736.
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BackgroundDisruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies.MethodElectronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review.ResultsResults for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) andToxoplasma gondiiwas mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia.ConclusionsPrenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a ‘sensitive period’ during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection.
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Mendel, D. B., T. Cihlar, K. Moon i M. S. Chen. "Conversion of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine to cidofovir by an intracellular cyclic CMP phosphodiesterase." Antimicrobial Agents and Chemotherapy 41, nr 3 (marzec 1997): 641–46. http://dx.doi.org/10.1128/aac.41.3.641.
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Cidofovir (HPMPC) [1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]-cytosine] is an acyclic nucleotide analog with potent and selective activity against herpesviruses. The prodrug, cyclic HPMPC (cHPMPC) [1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl) methyl]cytosine], has antiviral activity similar to that of the parent compound but exhibits reduced toxicity in animal models. cHPMPC is converted to cidofovir by a cellular cyclic CMP phosphodiesterase (EC 3.1.4.37) which hydrolyzes a variety of substrates, including adenosine 3',5'-cyclic monophosphate (cAMP) and cytidine 3',5'-cyclic monophosphate (cCMP). The K(m) and Vmax values for hydrolysis of cHPMPC by cCMP phosphodiesterase purified from human liver are 250 microM and 0.66 nmol.min-1.unit-1, respectively. These values are similar to the K(m) and Vmax values for cAMP (23 microM and 1.16 nmol.min-1.unit-1, respectively) and cCMP (75 microM and 2.32 nmol.min-1.unit of enzyme-1, respectively). The catalytic efficiency (Vmax/K(m) ratio) of this enzyme for the cHPMPC substrate is only 10- to 20-fold lower than those for the natural cyclic nucleotides, indicating that cHPMPC is a viable intracellular substrate for the human enzyme. Kinetic analysis indicates that cHPMPC, cAMP, and cCMP are competitive with respect to each other and that they are hydrolyzed by the same enzyme. cHPMPC is hydrolyzed to cidofovir in all primary human cell systems tested, including those derived from target organs that might be infected in patients with human cytomegalovirus (HCMV) disease. Importantly, hydrolysis of cHPMPC is not diminished in cells infected with HCMV.