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1
Mostafavi, Helen, Eranga Abeyratne, Ali Zaid, and Adam Taylor. "Arthritogenic Alphavirus-Induced Immunopathology and Targeting Host Inflammation as A Therapeutic Strategy for Alphaviral Disease." Viruses 11, no. 3 (March 22, 2019): 290. http://dx.doi.org/10.3390/v11030290.
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Arthritogenic alphaviruses are a group of medically important arboviruses that cause inflammatory musculoskeletal disease in humans with debilitating symptoms, such as arthralgia, arthritis, and myalgia. The arthritogenic, or Old World, alphaviruses are capable of causing explosive outbreaks, with some viruses of major global concern. At present, there are no specific therapeutics or commercially available vaccines available to prevent alphaviral disease. Infected patients are typically treated with analgesics and non-steroidal anti-inflammatory drugs to provide often inadequate symptomatic relief. Studies to determine the mechanisms of arthritogenic alphaviral disease have highlighted the role of the host immune system in disease pathogenesis. This review discusses the current knowledge of the innate immune response to acute alphavirus infection and alphavirus-induced immunopathology. Therapeutic strategies to treat arthritogenic alphavirus disease by targeting the host immune response are also examined.
2
Landers, V. Douglas, Daniel W. Wilkey, Michael L. Merchant, Thomas C. Mitchell, and Kevin J. Sokoloski. "The Alphaviral Capsid Protein Inhibits IRAK1-Dependent TLR Signaling." Viruses 13, no. 3 (February 27, 2021): 377. http://dx.doi.org/10.3390/v13030377.
Full textAbstract:
Alphaviruses are arthropod-borne RNA viruses which can cause either mild to severe febrile arthritis which may persist for months, or encephalitis which can lead to death or lifelong cognitive impairments. The non-assembly molecular role(s), functions, and protein–protein interactions of the alphavirus capsid proteins have been largely overlooked. Here we detail the use of a BioID2 biotin ligase system to identify the protein–protein interactions of the Sindbis virus capsid protein. These efforts led to the discovery of a series of novel host–pathogen interactions, including the identification of an interaction between the alphaviral capsid protein and the host IRAK1 protein. Importantly, this capsid–IRAK1 interaction is conserved across multiple alphavirus species, including arthritogenic alphaviruses SINV, Ross River virus, and Chikungunya virus; and encephalitic alphaviruses Eastern Equine Encephalitis virus, and Venezuelan Equine Encephalitis virus. The impact of the capsid–IRAK1 interaction was evaluated using a robust set of cellular model systems, leading to the realization that the alphaviral capsid protein specifically inhibits IRAK1-dependent signaling. This inhibition represents a means by which alphaviruses may evade innate immune detection and activation prior to viral gene expression. Altogether, these data identify novel capsid protein–protein interactions, establish the capsid–IRAK1 interaction as a common alphavirus host–pathogen interface, and delineate the molecular consequences of the capsid–IRAK1 interaction on IRAK1-dependent signaling.
3
Kaelber, Jason T., David Chmielewski, Wah Chiu, and Albert J. Auguste. "Alphavirus Particles Can Assemble with an Alternate Triangulation Number." Viruses 14, no. 12 (November 27, 2022): 2650. http://dx.doi.org/10.3390/v14122650.
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Alphaviruses are spherical, enveloped RNA viruses primarily transmitted by mosquitoes, and cause significant arthritogenic and neurotropic disease in humans and livestock. Previous reports have shown that—in contrast to prototypical icosahedral viruses—alphaviruses incorporate frequent defects, and these may serve important functions in the viral life cycle. We confirm the genus-wide pleomorphism in live viral particles and extend our understanding of alphavirus assembly through the discovery of an alternate architecture of Eastern equine encephalitis virus (EEEV) particles. The alternate T = 3 icosahedral architecture differs in triangulation number from the classic T = 4 icosahedral organization that typifies alphaviruses, but the alternate architecture maintains the quasi-equivalence relationship of asymmetric units. The fusion spike glycoproteins are more loosely apposed in the T = 3 form with corresponding changes in the underlying capsid protein lattice. This alternate architecture could potentially be exploited in engineering alphavirus-based particles for delivery of alphaviral or other RNA.
4
Bedoui, Yosra, Dauriane De Larichaudy, Matthieu Daniel, Franck Ah-Pine, Jimmy Selambarom, Pascale Guiraud, and Philippe Gasque. "Deciphering the Role of Schwann Cells in Inflammatory Peripheral Neuropathies Post Alphavirus Infection." Cells 12, no. 1 (December 26, 2022): 100. http://dx.doi.org/10.3390/cells12010100.
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Old world alphaviruses (e.g., chikungunya) are known to cause severe acute and chronic debilitating arthralgia/arthritis. However, atypical neurological manifestations and, in particular, unexpected cases of acute inflammatory Guillain–Barre syndrome (GBS) have been associated with the arthritogenic alphaviruses. The pathogenesis of alphavirus-associated GBS remains unclear. We herein addressed for the first time the role of Schwann cells (SC) in peripheral neuropathy post-alphaviral infection using the prototypical ONNV alphavirus model. We demonstrated that human SC expressed the recently identified alphavirus receptor MxRA8 and granting viral entry and robust replication. A canonical innate immune response was engaged by ONNV-infected SC with elevated gene expression for RIG-I, MDA5, IFN-β, and ISG15 and inflammatory chemokine CCL5. Transcription levels of prostaglandin E2-metabolizing enzymes including cPLA2α, COX-2, and mPGES-1 were also upregulated in ONNV-infected SC. Counterintuitively, we found that ONNV failed to affect SC regenerative properties as indicated by elevated expression of the pro-myelinating genes MPZ and MBP1 as well as the major pro-myelin transcription factor Egr2. While ONNV infection led to decreased expression of CD55 and CD59, essential to control complement bystander cytotoxicity, it increased TRAIL expression, a major pro-apoptotic T cell signal. Anti-apoptotic Bcl2 transcription levels were also increased in infected SC. Hence, our study provides new insights regarding the remarkable immunomodulatory role of SC of potential importance in the pathogenesis of GBS following alphavirus infection.
5
Cherkashchenko, Liubov, Kai Rausalu, Sanjay Basu, Luke Alphey, and Andres Merits. "Expression of Alphavirus Nonstructural Protein 2 (nsP2) in Mosquito Cells Inhibits Viral RNA Replication in Both a Protease Activity-Dependent and -Independent Manner." Viruses 14, no. 6 (June 17, 2022): 1327. http://dx.doi.org/10.3390/v14061327.
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Alphaviruses are positive-strand RNA viruses, mostly being mosquito-transmitted. Cells infected by an alphavirus become resistant to superinfection due to a block that occurs at the level of RNA replication. Alphavirus replication proteins, called nsP1-4, are produced from nonstructural polyprotein precursors, processed by the protease activity of nsP2. Trans-replicase systems and replicon vectors were used to study effects of nsP2 of chikungunya virus and Sindbis virus on alphavirus RNA replication in mosquito cells. Co-expressed wild-type nsP2 reduced RNA replicase activity of homologous virus; this effect was reduced but typically not abolished by mutation in the protease active site of nsP2. Mutations in the replicase polyprotein that blocked its cleavage by nsP2 reduced the negative effect of nsP2 co-expression, confirming that nsP2-mediated inhibition of RNA replicase activity is largely due to nsP2-mediated processing of the nonstructural polyprotein. Co-expression of nsP2 also suppressed the activity of replicases of heterologous alphaviruses. Thus, the presence of nsP2 inhibits formation and activity of alphavirus RNA replicase in protease activity-dependent and -independent manners. This knowledge improves our understanding about mechanisms of superinfection exclusion for alphaviruses and may aid the development of anti-alphavirus approaches.
6
Souza-Souza, Kauê F. C., Cassiano F. Gonçalves-de-Albuquerque, Cláudio Cirne-Santos, Izabel C. N. P. Paixão, and Patrícia Burth. "Alphavirus Replication: The Role of Cardiac Glycosides and Ion Concentration in Host Cells." BioMed Research International 2020 (May 9, 2020): 1–7. http://dx.doi.org/10.1155/2020/2813253.
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Alphaviruses are arthropod-borne viruses that can cause fever, rash, arthralgias, and encephalitis. The mosquito species Aedes aegypti and Aedes albopictus are the most frequent transmitters of alphaviruses. There are no effective vaccines or specific antivirals available for the treatment of alphavirus-related infections. Interestingly, changes in ion concentration in host cells have been characterized as critical regulators of the alphavirus life cycle, including fusion with the host cell, glycoprotein trafficking, genome translation, and viral budding. Cardiac glycosides, which are classical inhibitors of the Na+ K+ ATPase (NKA), can inhibit alphavirus replication although their mechanisms of action are poorly understood. Nonetheless, results from multiple studies suggest that inhibition of NKA may be a suitable strategy for the development of alphavirus-specific antiviral treatments. This review is aimed at exploring the role of changes in ion concentration during alphavirus replication and at considering the possibility of NKA as a potential therapeutic target for antiviral drugs.
7
Powers, Ann M., Aaron C. Brault, Yukio Shirako, Ellen G. Strauss, WenLi Kang, James H. Strauss, and Scott C. Weaver. "Evolutionary Relationships and Systematics of the Alphaviruses." Journal of Virology 75, no. 21 (November 1, 2001): 10118–31. http://dx.doi.org/10.1128/jvi.75.21.10118-10131.2001.
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ABSTRACT Partial E1 envelope glycoprotein gene sequences and complete structural polyprotein sequences were used to compare divergence and construct phylogenetic trees for the genus Alphavirus. Tree topologies indicated that the mosquito-borne alphaviruses could have arisen in either the Old or the New World, with at least two transoceanic introductions to account for their current distribution. The time frame for alphavirus diversification could not be estimated because maximum-likelihood analyses indicated that the nucleotide substitution rate varies considerably across sites within the genome. While most trees showed evolutionary relationships consistent with current antigenic complexes and species, several changes to the current classification are proposed. The recently identified fish alphaviruses salmon pancreas disease virus and sleeping disease virus appear to be variants or subtypes of a new alphavirus species. Southern elephant seal virus is also a new alphavirus distantly related to all of the others analyzed. Tonate virus and Venezuelan equine encephalitis virus strain 78V3531 also appear to be distinct alphavirus species based on genetic, antigenic, and ecological criteria. Trocara virus, isolated from mosquitoes in Brazil and Peru, also represents a new species and probably a new alphavirus complex.
8
Lundstrom, Kenneth. "Alphaviruses in Immunotherapy and Anticancer Therapy." Biomedicines 10, no. 9 (September 13, 2022): 2263. http://dx.doi.org/10.3390/biomedicines10092263.
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Alphaviruses have been engineered as expression vectors for vaccine development and gene therapy. Due to the feature of RNA self-replication, alphaviruses can provide exceptional direct cytoplasmic expression of transgenes based on the delivery of recombinant particles, naked or nanoparticle-encapsulated RNA or plasmid-based DNA replicons. Alphavirus vectors have been utilized for the expression of various antigens targeting different types of cancers, and cytotoxic and antitumor genes. The most common alphavirus vectors are based on the Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus, but the oncolytic M1 alphavirus has also been used. Delivery of immunostimulatory cytokine genes has been the basis for immunotherapy demonstrating efficacy in different animal tumor models for brain, breast, cervical, colon, lung, ovarian, pancreatic, prostate and skin cancers. Typically, therapeutic effects including tumor regression, tumor eradication and complete cure as well as protection against tumor challenges have been observed. Alphavirus vectors have also been subjected to clinical evaluations. For example, therapeutic responses in all cervical cancer patients treated with an alphavirus vector expressing the human papilloma virus E6 and E7 envelope proteins have been achieved.
9
Rao, Shambhavi, and Adam Taylor. "Arthritogenic Alphavirus Capsid Protein." Life 11, no. 3 (March 11, 2021): 230. http://dx.doi.org/10.3390/life11030230.
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In the past two decades Old World and arthritogenic alphavirus have been responsible for epidemics of polyarthritis, causing high morbidity and becoming a major public health concern. The multifunctional arthritogenic alphavirus capsid protein is crucial for viral infection. Capsid protein has roles in genome encapsulation, budding and virion assembly. Its role in multiple infection processes makes capsid protein an attractive target to exploit in combating alphaviral infection. In this review, we summarize the function of arthritogenic alphavirus capsid protein, and describe studies that have used capsid protein to develop novel arthritogenic alphavirus therapeutic and diagnostic strategies.
10
Nguyen, LeAnn P., Kelly S. Aldana, Emily Yang, Zhenlan Yao, and Melody M. H. Li. "Alphavirus Evasion of Zinc Finger Antiviral Protein (ZAP) Correlates with CpG Suppression in a Specific Viral nsP2 Gene Sequence." Viruses 15, no. 4 (March 24, 2023): 830. http://dx.doi.org/10.3390/v15040830.
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Certain re-emerging alphaviruses, such as chikungunya virus (CHIKV), cause serious disease and widespread epidemics. To develop virus-specific therapies, it is critical to understand the determinants of alphavirus pathogenesis and virulence. One major determinant is viral evasion of the host interferon response, which upregulates antiviral effectors, including zinc finger antiviral protein (ZAP). Here, we demonstrated that Old World alphaviruses show differential sensitivity to endogenous ZAP in 293T cells: Ross River virus (RRV) and Sindbis virus (SINV) are more sensitive to ZAP than o’nyong’nyong virus (ONNV) and CHIKV. We hypothesized that the more ZAP-resistant alphaviruses evade ZAP binding to their RNA. However, we did not find a correlation between ZAP sensitivity and binding to alphavirus genomic RNA. Using a chimeric virus, we found the ZAP sensitivity determinant lies mainly within the alphavirus non-structural protein (nsP) gene region. Surprisingly, we also did not find a correlation between alphavirus ZAP sensitivity and binding to nsP RNA, suggesting ZAP targeting of specific regions in the nsP RNA. Since ZAP can preferentially bind CpG dinucleotides in viral RNA, we identified three 500-bp sequences in the nsP region where CpG content correlates with ZAP sensitivity. Interestingly, ZAP binding to one of these sequences in the nsP2 gene correlated to sensitivity, and we confirmed that this binding is CpG-dependent. Our results demonstrate a potential strategy of alphavirus virulence by localized CpG suppression to evade ZAP recognition.
11
Henss, Lisa, Constanze Yue, Joshua Kandler, Helen M. Faddy, Graham Simmons, Marcus Panning, Lia Laura Lewis-Ximenez, Sally A. Baylis, and Barbara S. Schnierle. "Establishment of an Alphavirus-Specific Neutralization Assay to Distinguish Infections with Different Members of the Semliki Forest complex." Viruses 11, no. 1 (January 18, 2019): 82. http://dx.doi.org/10.3390/v11010082.
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Background: Alphaviruses are transmitted by arthropod vectors and can be found worldwide. Alphaviruses of the Semliki Forest complex such as chikungunya virus (CHIKV), Mayaro virus (MAYV) or Ross River virus (RRV) cause acute febrile illness and long-lasting arthralgia in humans, which cannot be clinically discriminated from a dengue virus or Zika virus infection. Alphaviruses utilize a diverse array of mosquito vectors for transmission and spread. For instance, adaptation of CHIKV to transmission by Aedes albopictus has increased its spread and resulted in large outbreaks in the Indian Ocean islands. For many alphaviruses commercial diagnostic tests are not available or show cross-reactivity among alphaviruses. Climate change and globalization will increase the spread of alphaviruses and monitoring of infections is necessary and requires virus-specific methods. Method: We established an alphavirus neutralization assay in a 384-well format by using pseudotyped lentiviral vectors. Results: MAYV-specific reactivity could be discriminated from CHIKV reactivity. Human plasma from blood donors infected with RRV could be clearly identified and did not cross-react with other alphaviruses. Conclusion: This safe and easy to use multiplex assay allows the discrimination of alphavirus-specific reactivity within a single assay and has potential for epidemiological surveillance. It might also be useful for the development of a pan-alphavirus vaccine.
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Rangel, Margarita V., and Kenneth A. Stapleford. "Alphavirus Virulence Determinants." Pathogens 10, no. 8 (August 3, 2021): 981. http://dx.doi.org/10.3390/pathogens10080981.
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Alphaviruses are important pathogens that continue to cause outbreaks of disease in humans and animals worldwide. Diseases caused by alphavirus infections include acute symptoms of fever, rash, and nausea as well as chronic arthritis and severe-to-fatal conditions including myocarditis and encephalitis. Despite their prevalence and the significant public health threat they pose, there are currently no effective antiviral treatments or vaccines against alphaviruses. Various genetic determinants of alphavirus virulence, including genomic RNA elements and specific protein residues and domains, have been described by researchers to play key roles in the development of disease, the immune response to infection, and virus transmissibility. Here, we focus on the determinants that are currently described in the literature. Understanding how these molecular determinants shape viral infections can lead to new strategies for the development of therapies and vaccines to combat these viruses.
13
Stepanov, Aleksandr V., Ilya V. Yudnikov, and Aleksandr V. Kvardakov. "Alphaviruses: a modern view on the problem." Bulletin of the Russian Military Medical Academy 24, no. 1 (April 20, 2022): 135–42. http://dx.doi.org/10.17816/brmma76901.
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At present, infectious diseases of alphaviral etiology remain relevant. The study examined the characteristics of alphaviruses, including the present knowledge of the structure and replication of the virion; prevalence of epidemiologically significant species and potential distribution areas of some alphaviruses; pathogenesis and clinical presentation of causative diseases, diagnosis, prevention, and treatment; and their possible use as pathogenic biological agents. Sixteen strains of alphaviruses are hazardous to human health, and some of them can disrupt human activities. Areas with alphaviruses are characterized by specific ecological conditions, presence of vectors, and susceptible hosts. Alphaviruses are predominantly distributed in equatorial and subequatorial belts. Some alphaviruses have been reported in the Russian Federation. The natural foci of alphaviruses are reportedly altered because of the expansion of their existing localizations, including the Russian territory. To predict the occurrence of alphavirus outbreaks, it is necessary to monitor pathogenic populations for mutations that can significantly increase their pathogenicity and virulence. Most alphaviruses, including those registered in Russia, do not have specific products for diagnostics, prevention, and treatment. Meanwhile, alphaviral diseases have great militaryepidemiological significance, as they can cause natural focal morbidity in certain regions of the world and injury to the civilian population and service personnel following their use as pathogenic biological agents.
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Lundstrom, Kenneth. "Plasmid DNA-based Alphavirus Vaccines." Vaccines 7, no. 1 (March 8, 2019): 29. http://dx.doi.org/10.3390/vaccines7010029.
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Alphaviruses have been engineered as vectors for high-level transgene expression. Originally, alphavirus-based vectors were applied as recombinant replication-deficient particles, subjected to expression studies in mammalian and non-mammalian cell lines, primary cell cultures, and in vivo. However, vector engineering has expanded the application range to plasmid DNA-based delivery and expression. Immunization studies with DNA-based alphavirus vectors have demonstrated tumor regression and protection against challenges with infectious agents and tumor cells in animal tumor models. The presence of the RNA replicon genes responsible for extensive RNA replication in the RNA/DNA layered alphavirus vectors provides superior transgene expression in comparison to conventional plasmid DNA-based expression. Immunization with alphavirus DNA vectors revealed that 1000-fold less DNA was required to elicit similar immune responses compared to conventional plasmid DNA. In addition to DNA-based delivery, immunization with recombinant alphavirus particles and RNA replicons has demonstrated efficacy in providing protection against lethal challenges by infectious agents and tumor cells.
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Malonis, Ryan J., James T. Earnest, Arthur S. Kim, Matthew Angeliadis, Frederick W. Holtsberg, M. Javad Aman, Rohit K. Jangra, et al. "Near-germline human monoclonal antibodies neutralize and protect against multiple arthritogenic alphaviruses." Proceedings of the National Academy of Sciences 118, no. 37 (September 10, 2021): e2100104118. http://dx.doi.org/10.1073/pnas.2100104118.
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Arthritogenic alphaviruses are globally distributed, mosquito-transmitted viruses that cause rheumatological disease in humans and include Chikungunya virus (CHIKV), Mayaro virus (MAYV), and others. Although serological evidence suggests that some antibody-mediated heterologous immunity may be afforded by alphavirus infection, the extent to which broadly neutralizing antibodies that protect against multiple arthritogenic alphaviruses are elicited during natural infection remains unknown. Here, we describe the isolation and characterization of MAYV-reactive alphavirus monoclonal antibodies (mAbs) from a CHIKV-convalescent donor. We characterized 33 human mAbs that cross-reacted with CHIKV and MAYV and engaged multiple epitopes on the E1 and E2 glycoproteins. We identified five mAbs that target distinct regions of the B domain of E2 and potently neutralize multiple alphaviruses with differential breadth of inhibition. These broadly neutralizing mAbs (bNAbs) contain few somatic mutations and inferred germline–revertants retained neutralizing capacity. Two bNAbs, DC2.M16 and DC2.M357, protected against both CHIKV- and MAYV-induced musculoskeletal disease in mice. These findings enhance our understanding of the cross-reactive and cross-protective antibody response to human alphavirus infections.
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La Linn, May, Joy Gardner, David Warrilow, Grant A. Darnell, Clive R. McMahon, Ian Field, Alex D. Hyatt, Robert W. Slade, and Andreas Suhrbier. "Arbovirus of Marine Mammals: a New Alphavirus Isolated from the Elephant Seal Louse, Lepidophthirus macrorhini." Journal of Virology 75, no. 9 (May 1, 2001): 4103–9. http://dx.doi.org/10.1128/jvi.75.9.4103-4109.2001.
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ABSTRACT A novel alphavirus was isolated from the louse Lepidophthirus macrorhini, collected from southern elephant seals,Mirounga leonina, on Macquarie Island, Australia. The virus displayed classic alphavirus ultrastructure and appeared to be serologically different from known Australasian alphaviruses. Nearly all Macquarie Island elephant seals tested had neutralizing antibodies against the virus, but no virus-associated pathology has been identified. Antarctic Division personnel who have worked extensively with elephant seals showed no serological evidence of exposure to the virus. Sequence analysis illustrated that the southern elephant seal (SES) virus segregates with the Semliki Forest group of Australasian alphaviruses. Phylogenetic analysis of known alphaviruses suggests that alphaviruses might be grouped according to their enzootic vertebrate host class. The SES virus represents the first arbovirus of marine mammals and illustrates that alphaviruses can inhabit Antarctica and that alphaviruses can be transmitted by lice.
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Torres-Ruesta, Anthony, Rhonda Sin-Ling Chee, and Lisa F. P. Ng. "Insights into Antibody-Mediated Alphavirus Immunity and Vaccine Development Landscape." Microorganisms 9, no. 5 (April 22, 2021): 899. http://dx.doi.org/10.3390/microorganisms9050899.
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Alphaviruses are mosquito-borne pathogens distributed worldwide in tropical and temperate areas causing a wide range of symptoms ranging from inflammatory arthritis-like manifestations to the induction of encephalitis in humans. Historically, large outbreaks in susceptible populations have been recorded followed by the development of protective long-lasting antibody responses suggesting a potential advantageous role for a vaccine. Although the current understanding of alphavirus antibody-mediated immunity has been mainly gathered in natural and experimental settings of chikungunya virus (CHIKV) infection, little is known about the humoral responses triggered by other emerging alphaviruses. This knowledge is needed to improve serology-based diagnostic tests and the development of highly effective cross-protective vaccines. Here, we review the role of antibody-mediated immunity upon arthritogenic and neurotropic alphavirus infections, and the current research efforts for the development of vaccines as a tool to control future alphavirus outbreaks.
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Luers, Aimée J., Sandra D. Adams, John V. Smalley, and James J. Campanella. "A Phylogenomic Study of the Genus Alphavirus Employing Whole Genome Comparison." Comparative and Functional Genomics 6, no. 4 (2005): 217–27. http://dx.doi.org/10.1002/cfg.478.
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The phylogenetics of the genus Alphavirus have historically been characterized using partial gene, single gene or partial proteomic data. We have mined cDNA and amino acid sequences from GenBank for all fully sequenced and some partially sequenced alphaviruses and generated phylogenomic analyses of the genus Alphavirus genus, employing capsid encoding structural regions, non-structural coding regions and complete viral genomes. Our studies support the presence of the previously reported recombination event that produced the Western Equine Encephalitis clade, and confirm many of the patterns of geographic radiation and divergence of the multiple species. Our data suggest that the Salmon Pancreatic Disease Virus and Sleeping Disease Virus are sufficiently divergent to form a separate clade from the other alphaviruses. Also, unlike previously reported studies employing limited sequence data for correlation of phylogeny, our results indicate that the Barmah Forest Virus and Middelburg Virus appear to be members of the Semliki Forest clade. Additionally, our analysis indicates that the Southern Elephant Seal Virus is part of the Semliki Forest clade, although still phylogenetically distant from all known members of the genus Alphavirus. Finally, we demonstrate that the whole Rubella viral genome provides an ideal outgroup for phylogenomic studies of the genus Alphavirus.
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Pampeno, Christine, Alicia Hurtado, Silvana Opp, and Daniel Meruelo. "Channeling the Natural Properties of Sindbis Alphavirus for Targeted Tumor Therapy." International Journal of Molecular Sciences 24, no. 19 (October 6, 2023): 14948. http://dx.doi.org/10.3390/ijms241914948.
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Sindbis alphavirus vectors offer a promising platform for cancer therapy, serving as valuable models for alphavirus-based treatment. This review emphasizes key studies that support the targeted delivery of Sindbis vectors to tumor cells, highlighting their effectiveness in expressing tumor-associated antigens and immunomodulating proteins. Among the various alphavirus vectors developed for cancer therapy, Sindbis-vector-based imaging studies have been particularly extensive. Imaging modalities that enable the in vivo localization of Sindbis vectors within lymph nodes and tumors are discussed. The correlation between laminin receptor expression, tumorigenesis, and Sindbis virus infection is examined. Additionally, we present alternative entry receptors for Sindbis and related alphaviruses, such as Semliki Forest virus and Venezuelan equine encephalitis virus. The review also discusses cancer treatments that are based on the alphavirus vector expression of anti-tumor agents, including tumor-associated antigens, cytokines, checkpoint inhibitors, and costimulatory immune molecules.
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Deperasińska, Izabela, Patrycja Schulz, and Andrzej K. Siwicki. "Salmonid alphavirus (SAV)." Journal of Veterinary Research 62, no. 1 (March 30, 2018): 1–6. http://dx.doi.org/10.2478/jvetres-2018-0001.
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AbstractSalmonid alphavirus (SAV), genus Alphavirus, family Togaviridae, is a single-stranded RNA virus affecting Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). It is known to be responsible for pancreas disease (PD) and sleeping disease (SD) which are increasing problems, causing high fish mortality and economic losses in the European aquaculture industry. Pancreas disease was first described in Atlantic salmon in Scotland in 1976 and a similar disease caused by the closely related sleeping disease virus was first described in rainbow trout in France. There have also been reports of salmonid alphavirus infections from other European countries, including Ireland, England, Norway, Germany, Italy, and Spain. Salmonid alphaviruses have been classified into six subtypes (SAV1–6). SAV1 and SAV4–6 cause pancreas disease in Atlantic salmon in Ireland or Scotland, SAV2 is the causative agent of sleeping disease in rainbow trout, and SAV3 has been detected in Atlantic salmon in Norway. The aim of this paper was to summarise current knowledge of infections caused by salmonid alphavirus and diagnostic methods including the newest techniques, and to briefly describe prevention from SAV infections by vaccination.
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Costlow, Jessica L., Erika S. Krow, and J. Jordan Steele. "Imatinib Mesylate as an Effective Anti-viral Treatment for Alphavirus Infections." Fine Focus 3, no. 2 (August 1, 2017): 141–52. http://dx.doi.org/10.33043/ff.3.2.141-152.
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Alphaviruses are plus-strand RNA viruses that are transmitted by mosquitoes. There are very limited vaccines and treatment options available to those infected with alphaviruses, resulting in significant human and animal morbidity and mortality each year. Viruses are parasites of host cell metabolism and alphaviruses have been shown to increase glycolytic flux during infection to aid viral replication. Imatinib mesylate is an FDA-approved tyrosine kinase inhibitor that is used to treat several types of cancers. A hallmark of tumorous cells is an elevated metabolic rate and Imatinib successfully slows metabolism by inhibiting tyrosine kinases that are required to activate metabolic enzymes, such as hexokinase in the glycolytic pathway. It was hypothesized that Imatinib could be used to slow metabolism in virally-infected cells and reduce viral replication. Alphavirus-infected cells were treated with various concentrations of Imatinib and at a concentration of 6 µM, viral replication was reduced by more than 40% while cell viability was still at 100%. The efficacy of Imatinib treatment at inhibiting alphavirus replication was confirmed at different times post infection (6, 12, 18, and 24 hours post infection), different levels of infection (multiplicities of infection= 0.1, 1, and 10), and within different cell lines (BHK, Huh7 and HEK). Further analysis in mouse or other animal models is needed to confirm the utility of Imatinib as a therapeutic option for treating alphavirus infection, but the data are promising and shows a significant reduction in viral replication and may represent a novel treatment option for alphavirus infections.
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Taylor, Adam, Julian V. Melton, Lara J. Herrero, Bastian Thaa, Liis Karo-Astover, Peter W. Gage, Michelle A. Nelson, et al. "Effects of an In-Frame Deletion of the6kGene Locus from the Genome of Ross River Virus." Journal of Virology 90, no. 8 (February 10, 2016): 4150–59. http://dx.doi.org/10.1128/jvi.03192-15.
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ABSTRACTThe alphaviral6kgene region encodes the two structural proteins 6K protein and, due to a ribosomal frameshift event, the transframe protein (TF). Here, we characterized the role of the6kproteins in the arthritogenic alphavirus Ross River virus (RRV) in infected cells and in mice, using a novel6kin-frame deletion mutant. Comprehensive microscopic analysis revealed that the6kproteins were predominantly localized at the endoplasmic reticulum of RRV-infected cells. RRV virions that lack the6kproteins 6K and TF [RRV-(Δ6K)] were more vulnerable to changes in pH, and the corresponding virus had increased sensitivity to a higher temperature. While the6kdeletion did not reduce RRV particle production in BHK-21 cells, it affected virion release from the host cell. Subsequentin vivostudies demonstrated that RRV-(Δ6K) caused a milder disease than wild-type virus, with viral titers being reduced in infected mice. Immunization of mice with RRV-(Δ6K) resulted in a reduced viral load and accelerated viral elimination upon secondary infection with wild-type RRV or another alphavirus, chikungunya virus (CHIKV). Our results show that the6kproteins may contribute to alphaviral disease manifestations and suggest that manipulation of the6kgene may be a potential strategy to facilitate viral vaccine development.IMPORTANCEArthritogenic alphaviruses, such as chikungunya virus (CHIKV) and Ross River virus (RRV), cause epidemics of debilitating rheumatic disease in areas where they are endemic and can emerge in new regions worldwide. RRV is of considerable medical significance in Australia, where it is the leading cause of arboviral disease. The mechanisms by which alphaviruses persist and cause disease in the host are ill defined. This paper describes the phenotypic properties of an RRV6kdeletion mutant. The absence of the6kgene reduced virion release from infected cells and also reduced the severity of disease and viral titers in infected mice. Immunization with the mutant virus protected mice against viremia not only upon exposure to RRV but also upon challenge with CHIKV. These findings could lead to the development of safer and more immunogenic alphavirus vectors for vaccine delivery.
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Tan, Yaw Bia, Laura Sandra Lello, Xin Liu, Yee-Song Law, Congbao Kang, Julien Lescar, Jie Zheng, Andres Merits, and Dahai Luo. "Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold." Nucleic Acids Research 50, no. 2 (January 17, 2022): 1000–1016. http://dx.doi.org/10.1093/nar/gkab1302.
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Abstract Alphaviruses such as Ross River virus (RRV), chikungunya virus (CHIKV), Sindbis virus (SINV), and Venezuelan equine encephalitis virus (VEEV) are mosquito-borne pathogens that can cause arthritis or encephalitis diseases. Nonstructural protein 4 (nsP4) of alphaviruses possesses RNA-dependent RNA polymerase (RdRp) activity essential for viral RNA replication. No 3D structure has been available for nsP4 of any alphaviruses despite its importance for understanding alphaviral RNA replication and for the design of antiviral drugs. Here, we report crystal structures of the RdRp domain of nsP4 from both RRV and SINV determined at resolutions of 2.6 Å and 1.9 Å. The structure of the alphavirus RdRp domain appears most closely related to RdRps from pestiviruses, noroviruses, and picornaviruses. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) methods showed that in solution, nsP4 is highly dynamic with an intrinsically disordered N-terminal domain. Both full-length nsP4 and the RdRp domain were capable to catalyze RNA polymerization. Structure-guided mutagenesis using a trans-replicase system identified nsP4 regions critical for viral RNA replication.
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Linn, May La, L. Mateo, J. Gardner, and A. Suhrbier. "Alphavirus-Specific Cytotoxic T Lymphocytes Recognize a Cross-Reactive Epitope from the Capsid Protein and Can Eliminate Virus from Persistently Infected Macrophages." Journal of Virology 72, no. 6 (June 1, 1998): 5146–53. http://dx.doi.org/10.1128/jvi.72.6.5146-5153.1998.
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ABSTRACT Persistent alphavirus infections in synovial and neural tissues are believed to be associated with chronic arthritis and encephalitis, respectively, and represent likely targets for CD8+ αβ cytotoxic T lymphocytes (CTL). Here we show that the capsid protein is a dominant target for alphavirus-specific CTL in BALB/c mice and that capsid-specific CTL from these mice recognize anH-2Kd restricted epitope, QYSGGRFTI. This epitope lies in the highly conserved region of the capsid protein, and QYSGGRFTI-specific CTL were cross reactive across a range of Old World alphaviruses. In vivo the acute primary viraemia of these highly cytopathic viruses was unaffected by QYSGGRFTI-specific CTL. However, in vitro these CTL were able to completely clear virus from macrophages persistently and productively infected with the arthrogenic alphavirus Ross River virus.
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Cappuccio, Lucie, and Carine Maisse. "Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death." Cells 9, no. 12 (December 5, 2020): 2612. http://dx.doi.org/10.3390/cells9122612.
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Alphaviruses, such as the chikungunya virus, are emerging and re-emerging viruses that pose a global public health threat. They are transmitted by blood-feeding arthropods, mainly mosquitoes, to humans and animals. Although alphaviruses cause debilitating diseases in mammalian hosts, it appears that they have no pathological effect on the mosquito vector. Alphavirus/host interactions are increasingly studied at cellular and molecular levels. While it seems clear that apoptosis plays a key role in some human pathologies, the role of cell death in determining the outcome of infections in mosquitoes remains to be fully understood. Here, we review the current knowledge on alphavirus-induced regulated cell death in hosts and vectors and the possible role they play in determining tolerance or resistance of mosquitoes.
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Herrero, Lara J., Suan-Sin Foo, Kuo-Ching Sheng, Weiqiang Chen, Mark R. Forwood, Richard Bucala, and Suresh Mahalingam. "Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of Alphavirus-Induced Cartilage Destruction and Inflammatory Disease." Journal of Virology 89, no. 15 (May 27, 2015): 8063–76. http://dx.doi.org/10.1128/jvi.00224-15.
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ABSTRACTArthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. Since its introduction in July 2014, CHIKV now circulates in the United States. The hallmark of alphavirus disease is crippling pain and inflammation of the joints, a similar immunopathology to rheumatoid arthritis. The use of glycans as novel therapeutics is an area of research that has increased in recent years. Here, we describe the promising therapeutic potential of the glycosaminoglycan (GAG)-like molecule pentosan polysulfate (PPS) to alleviate virus-induced arthritis. Mouse models of RRV and CHIKV disease were used to characterize the extent of cartilage damage in infection and investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR, and fluorescence-activated cell sorting (FACS). Alphaviral infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. The reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex bead arrays, PPS treatment was found to have significantly increased the anti-inflammatory cytokine interleukin-10 and reduced proinflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. PPS is a promising new therapy for alphavirus-induced arthritis, acting to preserve the cartilage matrix, which is damaged during alphavirus infection. Overall, the data demonstrate the potential of glycotherapeutics as a new class of treatment for infectious arthritis.IMPORTANCEThe hallmark of alphavirus disease is crippling pain and joint arthritis, which often has an extended duration. In the past year, CHIKV has expanded into the Americas, with approximately 1 million cases reported to date, whereas RRV continues to circulate in the South Pacific. Currently, there is no licensed specific treatment for alphavirus disease, and the increasing spread of infection highlights an urgent need for therapeutic intervention strategies. Pentosan polysulfate (PPS) is a glycan derivative that is orally bioavailable, has few toxic side effects, and is currently licensed under the name Elmiron for the treatment of cystitis in the United States. Our findings show that RRV infection damages the articular cartilage, including a loss of proteoglycans within the joint. Furthermore, treatment with PPS reduced the severity of both RRV- and CHIKV-induced musculoskeletal disease, including a reduction in inflammation and joint swelling, suggesting that PPS is a promising candidate for drug repurposing for the treatment of alphavirus-induced arthritis.
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Montgomery, Stephanie A., Peter Berglund, Clayton W. Beard, and Robert E. Johnston. "Ribosomal Protein S6 Associates with Alphavirus Nonstructural Protein 2 and Mediates Expression from Alphavirus Messages." Journal of Virology 80, no. 15 (August 1, 2006): 7729–39. http://dx.doi.org/10.1128/jvi.00425-06.
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ABSTRACT Although alphaviruses dramatically alter cellular function within hours of infection, interactions between alphaviruses and specific host cellular proteins are poorly understood. Although the alphavirus nonstructural protein 2 (nsP2) is an essential component of the viral replication complex, it also has critical auxiliary functions that determine the outcome of infection in the host. To gain a better understanding of nsP2 function, we sought to identify cellular proteins with which Venezuelan equine encephalitis virus nsP2 interacted. We demonstrate here that nsP2 associates with ribosomal protein S6 (RpS6) and that nsP2 is present in the ribosome-containing fractions of a polysome gradient, suggesting that nsP2 associates with RpS6 in the context of the whole ribosome. This result was noteworthy, since viral replicase proteins have seldom been described in direct association with components of the ribosome. The association of RpS6 with nsP2 was detected throughout the course of infection, and neither the synthesis of the viral structural proteins nor the presence of the other nonstructural proteins was required for RpS6 interaction with nsP2. nsP1 also was associated with RpS6, but other nonstructural proteins were not. RpS6 phosphorylation was dramatically diminished within hours after infection with alphaviruses. Furthermore, a reduction in the level of RpS6 protein expression led to diminished expression from alphavirus subgenomic messages, whereas no dramatic diminution in cellular translation was observed. Taken together, these data suggest that alphaviruses alter the ribosome during infection and that this alteration may contribute to differential translation of host and viral messages.
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Saha, Amrita, Badri Narayan Acharya, Manmohan Parida, Nandita Saxena, Jaya Rajaiya, and Paban Kumar Dash. "Identification of 2,4-Diaminoquinazoline Derivative as a Potential Small-Molecule Inhibitor against Chikungunya and Ross River Viruses." Viruses 15, no. 11 (October 31, 2023): 2194. http://dx.doi.org/10.3390/v15112194.
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Alphaviruses are serious zoonotic threats responsible for significant morbidity, causing arthritis or encephalitis. So far, no licensed drugs or vaccines are available to combat alphaviral infections. About 300,000 chikungunya virus (CHIKV) infections have been reported in 2023, with more than 300 deaths, including reports of a few cases in the USA as well. The discovery and development of small-molecule drugs have been revolutionized over the last decade. Here, we employed a cell-based screening approach using a series of in-house small-molecule libraries to test for their ability to inhibit CHIKV replication. DCR 137, a quinazoline derivative, was found to be the most potent inhibitor of CHIKV replication in our screening assay. Both, the cytopathic effect, and immunofluorescence of infected cells were reduced in a dose-dependent manner with DCR 137 post-treatment. Most importantly, DCR 137 was more protective than the traditional ribavirin drug and reduced CHIKV plaque-forming units by several log units. CHIKV-E2 protein levels were also reduced in a dose-dependent manner. Further, DCR 137 was probed for its antiviral activity against another alphavirus, the Ross River virus, which revealed effective inhibition of viral replication. These results led to the identification of a potential quinazoline candidate for future optimization that might act as a pan-alphavirus inhibitor.
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Azar, Sasha R., Rafael K. Campos, Nicholas A. Bergren, Vidyleison N. Camargos, and Shannan L. Rossi. "Epidemic Alphaviruses: Ecology, Emergence and Outbreaks." Microorganisms 8, no. 8 (August 1, 2020): 1167. http://dx.doi.org/10.3390/microorganisms8081167.
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Over the past century, the emergence/reemergence of arthropod-borne zoonotic agents has been a growing public health concern. In particular, agents from the genus Alphavirus pose a significant risk to both animal and human health. Human alphaviral disease presents with either arthritogenic or encephalitic manifestations and is associated with significant morbidity and/or mortality. Unfortunately, there are presently no vaccines or antiviral measures approved for human use. The present review examines the ecology, epidemiology, disease, past outbreaks, and potential to cause contemporary outbreaks for several alphavirus pathogens.
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Masika, Moses Muia, Essi M. Korhonen, Teemu Smura, Ruut Uusitalo, Joseph Ogola, Dufton Mwaengo, Anne J. Jääskeläinen, et al. "Serological Evidence of Exposure to Onyong-Nyong and Chikungunya Viruses in Febrile Patients of Rural Taita-Taveta County and Urban Kibera Informal Settlement in Nairobi, Kenya." Viruses 14, no. 6 (June 13, 2022): 1286. http://dx.doi.org/10.3390/v14061286.
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Several alphaviruses, such as chikungunya (CHIKV) and Onyong-nyong (ONNV), are endemic in Kenya and often cause outbreaks in different parts of the country. We assessed the seroprevalence of alphaviruses in patients with acute febrile illness in two geographically distant areas in Kenya with no previous record of alphavirus outbreaks. Blood samples were collected from febrile patients in health facilities located in the rural Taita-Taveta County in 2016 and urban Kibera informal settlement in Nairobi in 2017 and tested for CHIKV IgG and IgM antibodies using an in-house immunofluorescence assay (IFA) and a commercial ELISA test, respectively. A subset of CHIKV IgG or IgM antibody-positive samples were further analyzed using plaque reduction neutralization tests (PRNT) for CHIKV, ONNV, and Sindbis virus. Out of 537 patients, 4 (0.7%) and 28 (5.2%) had alphavirus IgM and IgG antibodies, respectively, confirmed on PRNT. We show evidence of previous and current exposure to alphaviruses based on serological testing in areas with no recorded history of outbreaks.
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Thibodeaux, Brett A., Nathan M. Liss, Amanda N. Panella, and John T. Roehrig. "Development of a Human-Murine Chimeric Immunoglobulin M for Use in the Serological Detection of Human Alphavirus Antibodies." Clinical and Vaccine Immunology 18, no. 12 (October 5, 2011): 2181–82. http://dx.doi.org/10.1128/cvi.05269-11.
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ABSTRACTDiagnosis of human alphaviral infections relies on serological techniques, such as the immunoglobulin M antibody capture–enzyme-linked immunosorbent assay (MAC-ELISA). We have humanized the alphavirus broadly cross-reactive murine monoclonal antibody 1A4B-6 to create a reagent capable of replacing human positive sera in the MAC-ELISA for diagnosis of human alphaviral infections.
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Zeng, Xiancheng, Suchetana Mukhopadhyay, and Charles L. Brooks. "Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion." Proceedings of the National Academy of Sciences 112, no. 7 (February 2, 2015): 2034–39. http://dx.doi.org/10.1073/pnas.1414190112.
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Alphavirus envelope proteins, organized as trimers of E2–E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections.
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Atkins, Gregory J. "The Pathogenesis of Alphaviruses." ISRN Virology 2013 (December 4, 2013): 1–22. http://dx.doi.org/10.5402/2013/861912.
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Alphaviruses are enveloped single-stranded positive sense RNA viruses of the family Togaviridae. The genus alphavirus contains nine viruses, which are of medical, theoretical, or economic importance, and which will be considered. Sindbis virus (SINV) and Semliki Forest (SFV), although of some medical importance, have largely been studied as models of viral pathogenicity. In mice, SINV and SFV infect neurons in the central nervous system and virulent strains induce lethal encephalitis, whereas avirulent strains of SFV induce demyelination. SFV infects the developing foetus and can be teratogenic. Venezuelan Equine Encephalitis virus, Eastern Equine Encephalitis virus, and Western Equine Encephalitis virus can induce encephalitis in horses and humans. They are prevalent in the Americas and are mosquito transmitted. Ross River virus, Chikungunya virus (CHIKV), and O’nyong-nyong virus (ONNV) are prevalent in Australasia, Africa and Asia, and Africa, respectively. ONNV virus is transmitted by Anopheles mosquitoes, while the other alphaviruses are transmitted by culicine mosquitoes. CHIKV has undergone adaptation to a new mosquito host which has increased its host range beyond Africa. Salmonid alphavirus is of economic importance in the farmed salmon and trout industry. It is postulated that future advances in research on alphavirus pathogenicity will come in the field of innate immunity.
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Sherman, Michael B., and Scott C. Weaver. "Structure of the Recombinant Alphavirus Western Equine Encephalitis Virus Revealed by Cryoelectron Microscopy." Journal of Virology 84, no. 19 (July 14, 2010): 9775–82. http://dx.doi.org/10.1128/jvi.00876-10.
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ABSTRACT Western equine encephalitis virus (WEEV; Togaviridae, Alphavirus) is an enveloped RNA virus that is typically transmitted to vertebrate hosts by infected mosquitoes. WEEV is an important cause of viral encephalitis in humans and horses in the Americas, and infection results in a range of disease, from mild flu-like illnesses to encephalitis, coma, and death. In addition to spreading via mosquito vectors, human WEEV infections can potentially occur directly via aerosol transmission. Due to its aerosol infectivity and virulence, WEEV is thus classified as a biological safety level 3 (BSL-3) agent. Because of its highly infectious nature and containment requirements, it has not been possible to investigate WEEV's structure or assembly mechanism using standard structural biology techniques. Thus, to image WEEV and other BSL-3 agents, we have constructed a first-of-its-kind BSL-3 cryoelectron microscopy (cryoEM) containment facility. cryoEM images of WEEV were used to determine the first three-dimensional structure of this important human pathogen. The overall organization of WEEV is similar to those of other alphaviruses, consistent with the high sequence similarity among alphavirus structural proteins. Surprisingly, the nucleocapsid of WEEV, a New World virus, is more similar to the Old World alphavirus Sindbis virus than to other New World alphaviruses.
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Basore, Katherine, James T. Earnest, Michael S. Diamond, and Daved H. Fremont. "Structural characterization of broadly neutralizing alphavirus antibodies." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 126.33. http://dx.doi.org/10.4049/jimmunol.200.supp.126.33.
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Abstract Mayaro is a mosquito-borne single-stranded positive RNA alphavirus endemic to tropical regions of South America. It is closely related to other arthritogenic alphaviruses, such as Chikungunya, Semliki Forest, Ross River, and Sindbis viruses. Although there are currently no available vaccines or therapies for alphaviruses, previous studies demonstrate that cross-protection between different alphaviruses could be mediated by antibodies that map to conserved epitopes. For example, a class of monoclonal antibodies against Chikungunya were recently shown to neutralize other alphaviruses by blocking viral entry and egress, all with epitopes on the surface E2 glycoprotein. A panel of antibodies generated against Mayaro infection and boosted with recombinate E2 protein were also found to be cross-neutralizing against other alphaviruses. Currently, epitope mapping and structural studies are being performed on these antibodies in order to determine the vital residues for binding, as well as to determine the mechanism of cross-neutralization.
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Treffers, Emmely E., Ali Tas, Florine E. M. Scholte, Arnoud H. de Ru, Eric J. Snijder, Peter A. van Veelen, and Martijn J. van Hemert. "The alphavirus nonstructural protein 2 NTPase induces a host translational shut-off through phosphorylation of eEF2 via cAMP-PKA-eEF2K signaling." PLOS Pathogens 19, no. 2 (February 27, 2023): e1011179. http://dx.doi.org/10.1371/journal.ppat.1011179.
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Chikungunya virus (CHIKV) is a reemerging alphavirus. Since 2005, it has infected millions of people during outbreaks in Africa, Asia, and South/Central America. CHIKV replication depends on host cell factors at many levels and is expected to have a profound effect on cellular physiology. To obtain more insight into host responses to infection, stable isotope labeling with amino acids in cell culture and liquid chromatography-tandem mass spectrometry were used to assess temporal changes in the cellular phosphoproteome during CHIKV infection. Among the ~3,000 unique phosphorylation sites analyzed, the largest change in phosphorylation status was measured on residue T56 of eukaryotic elongation factor 2 (eEF2), which showed a >50-fold increase at 8 and 12 h p.i. Infection with other alphaviruses (Semliki Forest, Sindbis and Venezuelan equine encephalitis virus (VEEV)) triggered a similarly strong eEF2 phosphorylation. Expression of a truncated form of CHIKV or VEEV nsP2, containing only the N-terminal and NTPase/helicase domains (nsP2-NTD-Hel), sufficed to induce eEF2 phosphorylation, which could be prevented by mutating key residues in the Walker A and B motifs of the NTPase domain. Alphavirus infection or expression of nsP2-NTD-Hel resulted in decreased cellular ATP levels and increased cAMP levels. This did not occur when catalytically inactive NTPase mutants were expressed. The wild-type nsP2-NTD-Hel inhibited cellular translation independent of the C-terminal nsP2 domain, which was previously implicated in directing the virus-induced host shut-off for Old World alphaviruses. We hypothesize that the alphavirus NTPase activates a cellular adenylyl cyclase resulting in increased cAMP levels, thus activating PKA and subsequently eukaryotic elongation factor 2 kinase. This in turn triggers eEF2 phosphorylation and translational inhibition. We conclude that the nsP2-driven increase of cAMP levels contributes to the alphavirus-induced shut-off of cellular protein synthesis that is shared between Old and New World alphaviruses. MS Data are available via ProteomeXchange with identifier PXD009381.
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Sousa, Ivanildo P., Carlos A. M. Carvalho, and Andre M. O. Gomes. "Current Understanding of the Role of Cholesterol in the Life Cycle of Alphaviruses." Viruses 13, no. 1 (December 29, 2020): 35. http://dx.doi.org/10.3390/v13010035.
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Enveloped viruses rely on different lipid classes present in cell membranes to accomplish several steps of their life cycle in the host. Particularly for alphaviruses, a medically important group of arboviruses, which are part of the Togaviridae family, cholesterol seems to be a critical lipid exploited during infection, although its relevance may vary depending on which stage of the virus life cycle is under consideration and whether infection takes place in vertebrate or invertebrate hosts. In this review, the role of cholesterol in both early and late events of alphavirus infection and how viral replication may affect cholesterol metabolism are summarized, taking into account studies on Old World and New World alphaviruses in different cell lines. Moreover, the importance of cholesterol for the structural stability of alphavirus particles is also discussed, shedding light on the role played by this lipid when they leave the host cell.
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Garmashova, Natalia, Rodion Gorchakov, Eugenia Volkova, Slobodan Paessler, Elena Frolova, and Ilya Frolov. "The Old World and New World Alphaviruses Use Different Virus-Specific Proteins for Induction of Transcriptional Shutoff." Journal of Virology 81, no. 5 (November 15, 2006): 2472–84. http://dx.doi.org/10.1128/jvi.02073-06.
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ABSTRACT Alphaviruses are widely distributed throughout the world. During the last few thousand years, the New World viruses, including Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), evolved separately from those of the Old World, i.e., Sindbis virus (SINV) and Semliki Forest virus (SFV). Nevertheless, the results of our study indicate that both groups have developed the same characteristic: their replication efficiently interferes with cellular transcription and the cell response to virus replication. Transcriptional shutoff caused by at least two of the Old World alphaviruses, SINV and SFV, which belong to different serological complexes, depends on nsP2, but not on the capsid protein, functioning. Our data suggest that the New World alphaviruses VEEV and EEEV developed an alternative mechanism of transcription inhibition that is mainly determined by their capsid protein, but not by the nsP2. The ability of the VEEV capsid to inhibit cellular transcription appears to be controlled by the amino-terminal fragment of the protein, but not by its protease activity or by the positively charged RNA-binding domain. These data provide new insights into alphavirus evolution and present a plausible explanation for the particular recombination events that led to the formation of western equine encephalitis virus (WEEV) from SINV- and EEEV-like ancestors. The recombination allowed WEEV to acquire capsid protein functioning in transcription inhibition from EEEV-like virus. Identification of the new functions in the New World alphavirus-derived capsids opens an opportunity for developing new, safer alphavirus-based gene expression systems and designing new types of attenuated vaccine strains of VEEV and EEEV.
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Ahola, Tero, Pekka Kujala, Minna Tuittila, Titta Blom, Pirjo Laakkonen, Ari Hinkkanen, and Petri Auvinen. "Effects of Palmitoylation of Replicase Protein nsP1 on Alphavirus Infection." Journal of Virology 74, no. 15 (August 1, 2000): 6725–33. http://dx.doi.org/10.1128/jvi.74.15.6725-6733.2000.
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ABSTRACT The membrane-associated alphavirus RNA replication complex contains four virus-encoded subunits, the nonstructural proteins nsP1 to nsP4. Semliki Forest virus (SFV) nsP1 is hydrophobically modified by palmitoylation of cysteines 418 to 420. Here we show that Sindbis virus nsP1 is also palmitoylated on the same site (cysteine 420). When mutations preventing nsP1 palmitoylation were introduced into the genomes of these two alphaviruses, the mutant viruses remained viable and replicated to high titers, although their growth was slightly delayed. The subcellular distribution of palmitoylation-defective nsP1 was altered in the mutant: it no longer localized to filopodial extensions, and a fraction of it was soluble. The ultrastructure of the alphavirus replication sites appeared normal, and the localization of the other nonstructural proteins was unaltered in the mutants. In both wild-type- and mutant-virus-infected cells, SFV nsP3 and nsP4 could be extracted from membranes only by alkaline solutions whereas the nsP2-membrane association was looser. Thus, the membrane binding properties of the alphavirus RNA replication complex were not determined by the palmitoylation of nsP1. The nsP1 palmitoylation-defective alphaviruses produced normal plaques in several cell types, but failed to give rise to plaques in HeLa cells, although they induced normal apoptosis of these cells. The SFV mutant was apathogenic in mice: it caused blood viremia, but no infectious virus was detected in the brain.
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Thibodeaux, Brett A., Amanda N. Panella, and John T. Roehrig. "Development of Human-Murine Chimeric Immunoglobulin G for Use in the Serological Detection of Human Flavivirus and Alphavirus Antibodies." Clinical and Vaccine Immunology 17, no. 10 (August 25, 2010): 1617–23. http://dx.doi.org/10.1128/cvi.00097-10.
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ABSTRACT Diagnosis of human arboviral infections relies heavily on serological techniques such as the immunoglobulin M (IgM) antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) and the indirect IgG ELISA. Broad application of these assays is hindered by the lack of standardized positive human control sera that react with a wide variety of flaviviruses (e.g., dengue, West Nile, yellow fever, Japanese encephalitis, Saint Louis encephalitis, and Powassan viruses), or alphaviruses (e.g., Eastern equine encephalitis, Western equine encephalitis, Venezuelan equine encephalitis, and chikungunya viruses) that can cause human disease. We have created human-murine chimeric monoclonal antibodies (cMAbs) by combining the variable regions of flavivirus (6B6C-1) or alphavirus (1A4B-6) broadly cross-reactive murine MAbs (mMAbs) with the constant region of human IgG1. These cMAbs may be used as standardized reagents capable of replacing human infection-immune-positive control sera in indirect IgG ELISA for diagnosis of all human flaviviral or alphaviral infections. The IgG cMAbs secreted from plasmid-transformed Sp2/0-Ag14 cells had serological activity identical to that of the parent mMAbs, as measured by ELISA using multiple flaviviruses or alphaviruses.
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Brown, Rebecca S., Lisa Kim, and Margaret Kielian. "Specific Recognition of a Stem-Loop RNA Structure by the Alphavirus Capsid Protein." Viruses 13, no. 8 (July 31, 2021): 1517. http://dx.doi.org/10.3390/v13081517.
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Alphaviruses are small enveloped viruses with positive-sense RNA genomes. During infection, the alphavirus capsid protein (Cp) selectively packages and assembles with the viral genomic RNA to form the nucleocapsid core, a process critical to the production of infectious virus. Prior studies of the alphavirus Semliki Forest virus (SFV) showed that packaging and assembly are promoted by Cp binding to multiple high affinity sites on the genomic RNA. Here, we developed an in vitro Cp binding assay based on fluorescently labeled RNA oligos. We used this assay to explore the RNA sequence and structure requirements for Cp binding to site #1, the top binding site identified on the genomic RNA during all stages of virus assembly. Our results identify a stem-loop structure that promotes specific binding of the SFV Cp to site #1 RNA. This structure is also recognized by the Cps of the related alphaviruses chikungunya virus and Ross River virus.
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Heise, Mark T., Dennis A. Simpson, and Robert E. Johnston. "Sindbis-Group Alphavirus Replication in Periosteum and Endosteum of Long Bones in Adult Mice." Journal of Virology 74, no. 19 (October 1, 2000): 9294–99. http://dx.doi.org/10.1128/jvi.74.19.9294-9299.2000.
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ABSTRACT Several alphaviruses, including the Sindbis-group viruses, Ross River virus, O'nyong-nyong virus, and Chikungunya virus, are associated with outbreaks of acute and persistent arthralgia and arthritis in humans. Mechanisms underlying alphavirus-induced arthralgia and arthritis are not clearly understood, though direct viral replication within or around the affected joints is thought to contribute to disease. S.A.AR86 is a Sindbis-group alphavirus closely related to the arthralgia-associated Ockelbo and GirdwoodS.A viruses. Following inoculation with S.A.AR86 derived from a molecular clone, infectious virus was isolated from bone and joint tissue 1 to 6 days postinfection. Studies using either in situ hybridization or S.A.AR86-derived double promoter viruses and replicons expressing green fluorescent protein localized sites of viral replication to the periosteum, tendons, and endosteum within the epiphyses of the long bones adjacent to articular joints. These results demonstrate that alphaviruses associated with arthralgia in humans replicate within bone-associated connective tissue adjacent to articular joints in an adult mouse model.
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Sokoloski, K. J., K. C. Haist, T. E. Morrison, S. Mukhopadhyay, and R. W. Hardy. "Noncapped Alphavirus Genomic RNAs and Their Role during Infection." Journal of Virology 89, no. 11 (April 1, 2015): 6080–92. http://dx.doi.org/10.1128/jvi.00553-15.
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ABSTRACTAlphaviruses are enveloped positive-sense RNA viruses that exhibit a wide host range consisting of vertebrate and invertebrate species. Previously we have reported that the infectivity of Sindbis virus (SINV), the model alphavirus, was largely a function of the cell line producing the viral particles. Mammalian-cell-derived SINV particles, on average, exhibit a higher particle-to-PFU ratio than mosquito cell-derived SINV particles. Nevertheless, the outcome of nonproductive infection, the molecular traits that determine particle infectivity and the biological importance of noninfectious particles were, prior to this study, unknown. Here, we report that the incoming genomic RNAs of noninfectious SINV particles undergo rapid degradation following infection. Moreover, these studies have led to the identification of the absence of the 5′ cap structure as a primary molecular determinant of particle infectivity. We show that the genomic RNAs of alphaviruses are not universally 5′ capped, with a significant number of noncapped genomic RNA produced early in infection. The production of noncapped viral genomic RNAs is important to the establishment and maintenance of alphaviral infection.IMPORTANCEThis report is of importance to the field of virology for three reasons. First, these studies demonstrate that noncapped Sindbis virus particles are produced as a result of viral RNA synthesis. Second, this report is, to our knowledge, the first instance of the direct measurement of the half-life of an incoming genomic RNA from a positive-sense RNA virus. Third, these studies indicate that alphaviral infection is likely a concerted effort of infectious and noninfectious viral particles.
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Elmasri, Zeinab, Benjamin L. Nasal, and Joyce Jose. "Alphavirus-Induced Membrane Rearrangements during Replication, Assembly, and Budding." Pathogens 10, no. 8 (August 4, 2021): 984. http://dx.doi.org/10.3390/pathogens10080984.
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Alphaviruses are arthropod-borne viruses mainly transmitted by hematophagous insects that cause moderate to fatal disease in humans and other animals. Currently, there are no approved vaccines or antivirals to mitigate alphavirus infections. In this review, we summarize the current knowledge of alphavirus-induced structures and their functions in infected cells. Throughout their lifecycle, alphaviruses induce several structural modifications, including replication spherules, type I and type II cytopathic vacuoles, and filopodial extensions. Type I cytopathic vacuoles are replication-induced structures containing replication spherules that are sites of RNA replication on the endosomal and lysosomal limiting membrane. Type II cytopathic vacuoles are assembly induced structures that originate from the Golgi apparatus. Filopodial extensions are induced at the plasma membrane and are involved in budding and cell-to-cell transport of virions. This review provides an overview of the viral and host factors involved in the biogenesis and function of these virus-induced structures. Understanding virus–host interactions in infected cells will lead to the identification of new targets for antiviral discovery.
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Behnia, Mahgol, and Steven B. Bradfute. "The Host Non-Coding RNA Response to Alphavirus Infection." Viruses 15, no. 2 (February 18, 2023): 562. http://dx.doi.org/10.3390/v15020562.
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Alphaviruses are important human and animal pathogens that can cause a range of debilitating symptoms and are found worldwide. These include arthralgic diseases caused by Old-World viruses and encephalitis induced by infection with New-World alphaviruses. Non-coding RNAs do not encode for proteins, but can modulate cellular response pathways in a myriad of ways. There are several classes of non-coding RNAs, some more well-studied than others. Much research has focused on the mRNA response to infection against alphaviruses, but analysis of non-coding RNA responses has been more limited until recently. This review covers what is known regarding host cell non-coding RNA responses in alphavirus infections and highlights gaps in the knowledge that future research should address.
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Wu, Josh QH, Nicole D. Barabé, and Damon Chau. "Effect of exogenous expression of IFN-γ on the new world alphavirus replication and infection." Future Virology 14, no. 9 (September 2019): 593–604. http://dx.doi.org/10.2217/fvl-2019-0073.
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Aim: IFN-γ plays an important role in control of the old world alphavirus infection. However, the role of IFN-γ in the infection by the new world alphaviruses is not well characterized. Materials & methods: Ad5-mIFN-γ, a recombinant, replication-deficient human adenovirus, was constructed to express mouse IFN-γ (mIFN-γ) and a mouse, lethal challenge model of the new world alphavirus western equine encephalitis virus (WEEV) was used. Results: A single-dose injection of Ad5-mIFN-γ produced a high level of mIFN-γ in mice. Cells inoculated with Ad5-mIFN-γ restricted the replication of WEEV. A single-dose injection of Ad5-mIFN-γ delayed the WEEV infection and extended the survival time in mice. Conclusion: IFN-γ restricts the WEEV infection.
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Nasar, Farooq, Rodion V. Gorchakov, Robert B. Tesh, and Scott C. Weaver. "Eilat Virus Host Range Restriction Is Present at Multiple Levels of the Virus Life Cycle." Journal of Virology 89, no. 2 (November 12, 2014): 1404–18. http://dx.doi.org/10.1128/jvi.01856-14.
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ABSTRACTMost alphaviruses are mosquito-borne and exhibit a broad host range, infecting many different vertebrates, including birds, rodents, equids, humans, and nonhuman primates. This ability of most alphaviruses to infect arthropods and vertebrates is essential for their maintenance in nature. Recently, a new alphavirus, Eilat virus (EILV), was described, and in contrast to all other mosquito-borne viruses, it is unable to replicate in vertebrate cell lines. Investigations into the nature of its host range restriction showed the inability of genomic EILV RNA to replicate in vertebrate cells. Here, we investigated whether the EILV host range restriction is present at the entry level and further explored the viral factors responsible for the lack of genomic RNA replication. Utilizing Sindbis virus (SINV) and EILV chimeras, we show that the EILV vertebrate host range restriction is also manifested at the entry level. Furthermore, the EILV RNA replication restriction is independent of the 3′ untranslated genome region (UTR). Complementation experiments with SINV suggested that RNA replication is restricted by the inability of the EILV nonstructural proteins to form functional replicative complexes. These data demonstrate that the EILV host range restriction is multigenic, involving at least one gene from both nonstructural protein (nsP) and structural protein (sP) open reading frames (ORFs). As EILV groups phylogenetically within the mosquito-borne virus clade of pathogenic alphaviruses, our findings have important evolutionary implications for arboviruses.IMPORTANCEOur work explores the nature of host range restriction of the first “mosquito-only alphavirus,” EILV. EILV is related to pathogenic mosquito-borne viruses (Eastern equine encephalitis virus [EEEV], Western equine encephalitis virus [WEEV], Venezuelan equine encephalitis virus [VEEV], and Chikungunya virus [CHIKV]) that cause severe disease in humans. Our data demonstrate that EILV is restricted both at entry and genomic RNA replication levels in vertebrate cells. These findings have important implications for arbovirus evolution and will help elucidate the viral factors responsible for the broad host range of pathogenic mosquito-borne alphaviruses, facilitate vaccine development, and inform potential strategies to reduce/prevent alphavirus transmission.
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Villoing, Stéphane, Monique Béarzotti, Stefan Chilmonczyk, Jeannette Castric, and Michel Brémont. "Rainbow Trout Sleeping Disease Virus Is an Atypical Alphavirus." Journal of Virology 74, no. 1 (January 1, 2000): 173–83. http://dx.doi.org/10.1128/jvi.74.1.173-183.2000.
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ABSTRACT Sleeping disease (SD) is currently a matter of concern for salmonid fish farmers in most parts of the world. A viral etiology of SD has recently been suspected, since virus-like particles have been observed in infected rainbow trout cells. In salmonid-derived cell lines, the maximal rate of virus production was observed at 10°C, while little virus was produced at 14°C. Through biochemical, physicochemical, and morphological studies, SD virus (SDV) was shown to be an enveloped virus of roughly 60 nm in diameter. The genome consists of 12 kb of RNA, with the appearance of a 26S subgenomic RNA during the time course of SDV replication. The screening of a random-primed cDNA library constructed from the genomic RNA of semipurified virions facilitated the identification of a specific SDV cDNA clone having an open reading frame related to the alphavirus E2 glycoproteins. To extend the comparison between SDV structural proteins and the alphavirus protein counterparts, the nucleotide sequence of the total 4.1-kb subgenomic RNA has been determined. The 26S RNA encodes a 1,324-amino-acid polyprotein exhibiting typical alphavirus structural protein organization. SDV structural proteins showed several remarkable features compared to other alphaviruses: (i) unusually large individual proteins, (ii) very low homology (ranging from 30 to 34%) (iii) an unglycosylated E3 protein, and (iv) and E1 fusion domain sharing mutations implicated in the pH threshold. Although phylogenetically related to the Semliki Forest virus group of alphaviruses, SDV should be considered an atypical member, able to naturally replicate in lower vertebrates.
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Simmons, Jason D., Laura J. White, Thomas E. Morrison, Stephanie A. Montgomery, Alan C. Whitmore, Robert E. Johnston, and Mark T. Heise. "Venezuelan Equine Encephalitis Virus Disrupts STAT1 Signaling by Distinct Mechanisms Independent of Host Shutoff." Journal of Virology 83, no. 20 (August 5, 2009): 10571–81. http://dx.doi.org/10.1128/jvi.01041-09.
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ABSTRACT Venezuelan equine encephalitis virus (VEEV) is an important human and veterinary pathogen causing sporadic epizootic outbreaks of potentially fatal encephalitis. The type I interferon (IFN) system plays a central role in controlling VEEV and other alphavirus infections, and IFN evasion is likely an important determinant of whether these viruses disseminate and cause disease within their hosts. Alphaviruses are thought to limit the induction of type I IFNs and IFN-stimulated genes by shutting off host cell macromolecular synthesis, which in the case of VEEV is partially mediated by the viral capsid protein. However, more specific strategies by which alphaviruses inhibit type I IFN signaling have not been characterized. Analyses of cells infected with VEEV and VEEV replicon particles (VRP) demonstrate that viral infection rapidly disrupts tyrosine phosphorylation and nuclear translocation of the transcription factor STAT1 in response to both IFN-β and IFN-γ. This effect was independent of host shutoff and expression of viral capsid, suggesting that VEEV uses novel mechanisms to interfere with type I and type II IFN signaling. Furthermore, at times when STAT1 activation was efficiently inhibited, VRP infection did not limit tyrosine phosphorylation of Jak1, Tyk2, or STAT2 after IFN-β treatment but did inhibit Jak1 and Jak2 activation in response to IFN-γ, suggesting that VEEV interferes with STAT1 activation by the type I and II receptor complexes through distinct mechanisms. Identification of the viral requirements for this novel STAT1 inhibition will further our understanding of alphavirus molecular pathogenesis and may provide insights into effective alphavirus-based vaccine design.
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Poddar, Subhajit, Jennifer L. Hyde, Matthew J. Gorman, Michael Farzan, and Michael S. Diamond. "The Interferon-Stimulated Gene IFITM3 Restricts Infection and Pathogenesis of Arthritogenic and Encephalitic Alphaviruses." Journal of Virology 90, no. 19 (July 20, 2016): 8780–94. http://dx.doi.org/10.1128/jvi.00655-16.
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ABSTRACTHost cells respond to viral infections by producing type I interferon (IFN), which induces the expression of hundreds of interferon-stimulated genes (ISGs). Although ISGs mediate a protective state against many pathogens, the antiviral functions of the majority of these genes have not been identified. IFITM3 is a small transmembrane ISG that restricts a broad range of viruses, including orthomyxoviruses, flaviviruses, filoviruses, and coronaviruses. Here, we show that alphavirus infection is increased inIfitm3−/−andIfitmlocus deletion (Ifitm-del) fibroblasts and, reciprocally, reduced in fibroblasts transcomplemented with Ifitm3. Mechanistic studies showed that Ifitm3 did not affect viral binding or entry but inhibited pH-dependent fusion. In a murine model of chikungunya virus arthritis,Ifitm3−/−mice sustained greater joint swelling in the ipsilateral ankle at days 3 and 7 postinfection, and this correlated with higher levels of proinflammatory cytokines and viral burden. Flow cytometric analysis suggested thatIfitm3−/−macrophages from the spleen were infected at greater levels than observed in wild-type (WT) mice, results that were supported by experiments withIfitm3−/−bone marrow-derived macrophages.Ifitm3−/−mice also were more susceptible than WT mice to lethal alphavirus infection with Venezuelan equine encephalitis virus, and this was associated with greater viral burden in multiple organs. Collectively, our data define an antiviral role for Ifitm3 in restricting infection of multiple alphaviruses.IMPORTANCEThe interferon-induced transmembrane protein 3 (IFITM3) inhibits infection of multiple families of viruses in cell culture. Compared to other viruses, much less is known about the antiviral effect of IFITM3 on alphaviruses. In this study, we characterized the antiviral activity of mouse Ifitm3 against arthritogenic and encephalitic alphaviruses using cells and animals with a targeted gene deletion ofIfitm3as well as deficient cells transcomplemented with Ifitm3. Based on extensive virological analysis, we demonstrate greater levels of alphavirus infection and disease pathogenesis when Ifitm3 expression is absent. Our data establish an inhibitory role for Ifitm3 in controlling infection of alphaviruses.