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PLoS Pathogens Oct 2020Alphaviruses cause severe human illnesses including persistent arthritis and fatal encephalitis. As alphavirus entry into target cells is the first step in infection,... (Review)
Review
Alphaviruses cause severe human illnesses including persistent arthritis and fatal encephalitis. As alphavirus entry into target cells is the first step in infection, intensive research efforts have focused on elucidating aspects of this pathway, including attachment, internalization, and fusion. Herein, we review recent developments in the molecular understanding of alphavirus entry both in vitro and in vivo and how these advances might enable the design of therapeutics targeting this critical step in the alphavirus life cycle.
Topics: Alphavirus; Alphavirus Infections; Animals; Host-Pathogen Interactions; Humans; Virus Internalization; Virus Replication
PubMed: 33091085
DOI: 10.1371/journal.ppat.1008876 -
Journal of Virology Jun 2018Alphaviruses are transmitted to humans via bites of infected mosquitoes. Although alphaviruses have caused a wide range of outbreaks and crippling disease, the... (Review)
Review
Alphaviruses are transmitted to humans via bites of infected mosquitoes. Although alphaviruses have caused a wide range of outbreaks and crippling disease, the availability of licensed vaccines or antiviral therapies remains limited. Mosquito vectors such as and are the main culprits in the transmission of alphaviruses. This review explores how mosquito saliva may promote alphavirus infection. Identifying the roles of mosquito-derived factors in alphavirus pathogenesis will generate novel tools to circumvent and control mosquito-borne alphavirus infections in humans.
Topics: Adaptive Immunity; Aedes; Alphavirus; Alphavirus Infections; Animals; Culex; Humans; Immunity, Innate; Immunosuppression Therapy; Saliva; Skin
PubMed: 29593049
DOI: 10.1128/JVI.01004-17 -
Nature Communications Oct 2023Arthritogenic alphaviruses are positive-strand RNA viruses that cause debilitating musculoskeletal diseases affecting millions worldwide. A recent discovery identified...
Arthritogenic alphaviruses are positive-strand RNA viruses that cause debilitating musculoskeletal diseases affecting millions worldwide. A recent discovery identified the four-and-a-half-LIM domain protein 1 splice variant A (FHL1A) as a crucial host factor interacting with the hypervariable domain (HVD) of chikungunya virus (CHIKV) nonstructural protein 3 (nsP3). Here, we show that acute and chronic chikungunya disease in humans correlates with elevated levels of FHL1. We generated FHL1 mice, which when infected with CHIKV or o'nyong-nyong virus (ONNV) displayed reduced arthritis and myositis, fewer immune infiltrates, and reduced proinflammatory cytokine/chemokine outputs, compared to infected wild-type (WT) mice. Interestingly, disease signs were comparable in FHL1 and WT mice infected with arthritogenic alphaviruses Ross River virus (RRV) or Mayaro virus (MAYV). This aligns with pull-down assay data, which showed the ability of CHIKV and ONNV nsP3 to interact with FHL1, while RRV and MAYV nsP3s did not. We engineered a CHIKV mutant unable to bind FHL1 (CHIKV-ΔFHL1), which was avirulent in vivo. Following inoculation with CHIKV-ΔFHL1, mice were protected from disease upon challenge with CHIKV and ONNV, and viraemia was significantly reduced in RRV- and MAYV-challenged mice. Targeting FHL1-binding as an approach to vaccine design could lead to breakthroughs in mitigating alphaviral disease.
Topics: Animals; Humans; Mice; Arthritis; Chikungunya Fever; Chikungunya virus; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Muscle Proteins; O'nyong-nyong Virus; Vaccines
PubMed: 37884534
DOI: 10.1038/s41467-023-42330-2 -
Emerging Microbes & Infections Sep 2018Mayaro virus (MAYV), an enveloped RNA virus, belongs to the Togaviridae family and Alphavirus genus. This arthropod-borne virus (Arbovirus) is similar to Chikungunya... (Review)
Review
Mayaro virus (MAYV), an enveloped RNA virus, belongs to the Togaviridae family and Alphavirus genus. This arthropod-borne virus (Arbovirus) is similar to Chikungunya (CHIKV), Dengue (DENV), and Zika virus (ZIKV). The term "ChikDenMaZika syndrome" has been coined for clinically suspected arboviruses, which have arisen as a consequence of the high viral burden, viral co-infection, and co-circulation in South America. In most cases, MAYV disease is nonspecific, mild, and self-limited. Fever, arthralgia, and maculopapular rash are among the most common symptoms described, being largely indistinguishable from those caused by other arboviruses. However, severe manifestations of the infection have been reported, such as chronic polyarthritis, neurological complications, hemorrhage, myocarditis, and even death. Currently, there are no specific commercial tools for the diagnosis of MAYV, and the use of serological methods can be affected by cross-reactivity and the window period. A diagnosis based on clinical and epidemiological data alone is still premature. Therefore, new entomological research is warranted, and new highly specific molecular diagnostic methods should be developed. This comprehensive review is intended to encourage public health authorities and scientific communities to actively work on diagnosing, preventing, and treating MAYV infection.
Topics: Alphavirus; Alphavirus Infections; Animals; Communicable Diseases, Emerging; Humans; South America
PubMed: 30254258
DOI: 10.1038/s41426-018-0163-5 -
Viruses Jan 2023Eastern (EEEV), Venezuelan (VEEV), and western equine encephalitis viruses (WEEV) are members of the genus , family . Typically spread by mosquitoes, EEEV, VEEV, and... (Review)
Review
Eastern (EEEV), Venezuelan (VEEV), and western equine encephalitis viruses (WEEV) are members of the genus , family . Typically spread by mosquitoes, EEEV, VEEV, and WEEV induce febrile illness that may develop into more severe encephalitic disease, resulting in myriad severe neurologic sequelae for which there are no vaccines or therapeutics. Here, we summarize the clinical neurologic findings and sequelae induced by these three encephalitic viruses and describe the various animal models available to study them. We emphasize the crucial need for the development of advanced animal modeling combined with the use of telemetry, behavioral testing, and neuroimaging to facilitate a detailed mechanistic understanding of these encephalitic signs and sequelae. Through the use of these systems, much-needed therapeutics and vaccines can be developed.
Topics: Animals; Horses; Alphavirus; Encephalitis; Alphavirus Infections; Encephalitis Virus, Western Equine; Disease Progression; Models, Animal
PubMed: 36851596
DOI: 10.3390/v15020382 -
Frontiers in Immunology 2022Alphaviruses contain many human and animal pathogens, such as CHIKV, SINV, and VEEV. Accumulating evidence indicates that innate immunity plays an important role in... (Review)
Review
Alphaviruses contain many human and animal pathogens, such as CHIKV, SINV, and VEEV. Accumulating evidence indicates that innate immunity plays an important role in response to alphaviruses infection. In parallel, alphaviruses have evolved many strategies to evade host antiviral innate immunity. In the current review, we focus on the underlying mechanisms employed by alphaviruses to evade cGAS-STING, IFN, transcriptional host shutoff, translational host shutoff, and RNAi. Dissecting the detailed antiviral immune evasion mechanisms by alphaviruses will enhance our understanding of the pathogenesis of alphaviruses and may provide more effective strategies to control alphaviruses infection.
Topics: Alphavirus; Alphavirus Infections; Animals; Antiviral Agents; Humans; Immune Evasion; Nucleotidyltransferases
PubMed: 36172361
DOI: 10.3389/fimmu.2022.1005586 -
The Journal of Clinical Investigation Jan 2023Alphaviruses are enveloped, insect-transmitted, positive-sense RNA viruses that infect humans and other animals and cause a range of clinical manifestations, including... (Review)
Review
Alphaviruses are enveloped, insect-transmitted, positive-sense RNA viruses that infect humans and other animals and cause a range of clinical manifestations, including arthritis, musculoskeletal disease, meningitis, encephalitis, and death. Over the past four years, aided by CRISPR/Cas9-based genetic screening approaches, intensive research efforts have focused on identifying entry receptors for alphaviruses to better understand the basis for cellular and species tropism. Herein, we review approaches to alphavirus receptor identification and how these were used for discovery. The identification of new receptors advances our understanding of viral pathogenesis, tropism, and evolution and is expected to contribute to the development of novel strategies for prevention and treatment of alphavirus infection.
Topics: Animals; Humans; Alphavirus Infections; Alphavirus
PubMed: 36647825
DOI: 10.1172/JCI165307 -
Mammalian Genome : Official Journal of... Aug 2018Alphaviruses, members of the positive-sense, single-stranded RNA virus family Togaviridae, represent a re-emerging public health concern worldwide as mosquito vectors... (Review)
Review
Alphaviruses, members of the positive-sense, single-stranded RNA virus family Togaviridae, represent a re-emerging public health concern worldwide as mosquito vectors expand into new geographic ranges. Members of the alphavirus genus tend to induce clinical disease characterized by rash, arthralgia, and arthritis (chikungunya virus, Ross River virus, and Semliki Forest virus) or encephalomyelitis (eastern equine encephalitis virus, western equine encephalitis virus, and Venezuelan equine encephalitis virus), though some patients who recover from the initial acute illness may develop long-term sequelae, regardless of the specific infecting virus. Studies examining the natural disease course in humans and experimental infection in cell culture and animal models reveal that host genetics play a major role in influencing susceptibility to infection and severity of clinical disease. Genome-wide genetic screens, including loss of function screens, microarrays, RNA-sequencing, and candidate gene studies, have further elucidated the role host genetics play in the response to virus infection, with the immune response being found in particular to majorly influence the outcome. This review describes the current knowledge of the mechanisms by which host genetic factors influence alphavirus pathogenesis and discusses emerging technologies that are poised to increase our understanding of the complex interplay between viral and host genetics on disease susceptibility and clinical outcome.
Topics: Alphavirus; Alphavirus Infections; Animals; Arthropods; Biomarkers; Disease Models, Animal; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Host-Pathogen Interactions; Humans
PubMed: 30151711
DOI: 10.1007/s00335-018-9776-1 -
Veterinary Microbiology Jan 2010This review will cover zoonotic, encephalitic alphaviruses in the family Togaviridae. Encephalitic alphaviruses, i.e. Western- (WEEV), Eastern- (EEEV), Venezuelan equine... (Review)
Review
This review will cover zoonotic, encephalitic alphaviruses in the family Togaviridae. Encephalitic alphaviruses, i.e. Western- (WEEV), Eastern- (EEEV), Venezuelan equine encephalitis virus (VEEV) and, more rarely, Ross River virus, Chikungunya virus and Highlands J virus (HJV), are neuroinvasive and may cause neurological symptoms ranging from mild (e.g., febrile illness) to severe (e.g., encephalitis) in humans and equines. Among the naturally occurring alphaviruses, WEEV, EEEV and VEEV have widespread distributions in North, Central and South America. WEEV has found spanning the U.S. from the mid-West (Michigan and Illinois) to the West coast and extending to Canada with human cases reported in 21 states. EEEV is found along the Gulf (Texas to Florida) and Atlantic Coast (Georgia to New Hampshire), as well as in the mid-West (Wisconsin, Illinois and Michigan) and in Canada, with human cases reported in 19 states. In contrast, transmission of VEEV occurs predominantly in Central and South America. As with their geographical distribution, equine encephalitis viruses differ in their main mosquito vector species and their zoonotic potential.
Topics: Alphavirus; Alphavirus Infections; Americas; Animals; Encephalitis, Viral; Geography; Horse Diseases; Horses; Humans; Zoonoses
PubMed: 19775836
DOI: 10.1016/j.vetmic.2009.08.023 -
Annual Review of Immunology Apr 2022Alphaviruses are emerging and reemerging viruses that cause disease syndromes ranging from incapacitating arthritis to potentially fatal encephalitis. While infection by... (Review)
Review
Alphaviruses are emerging and reemerging viruses that cause disease syndromes ranging from incapacitating arthritis to potentially fatal encephalitis. While infection by arthritogenic and encephalitic alphaviruses results in distinct clinical manifestations, both virus groups induce robust innate and adaptive immune responses. However, differences in cellular tropism, type I interferon induction, immune cell recruitment, and B and T cell responses result in differential disease progression and outcome. In this review, we discuss aspects of immune responses that contribute to protective or pathogenic outcomes after alphavirus infection.
Topics: Alphavirus; Alphavirus Infections; Animals; Humans; Immunity; Interferon Type I; Tropism
PubMed: 35134315
DOI: 10.1146/annurev-immunol-101220-014952