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Antiviral Research Jan 2023The alphaviruses are a widely distributed group of positive-sense, single stranded, RNA viruses. These viruses are largely arthropod-borne and can be found on all... (Review)
Review
The alphaviruses are a widely distributed group of positive-sense, single stranded, RNA viruses. These viruses are largely arthropod-borne and can be found on all populated continents. These viruses cause significant human disease, and recently have begun to spread into new populations, such as the expansion of Chikungunya virus into southern Europe and the Caribbean, where it has established itself as endemic. The study of alphaviruses is an active and expanding field, due to their impacts on human health, their effects on agriculture, and the threat that some pose as potential agents of biological warfare and terrorism. In this systematic review we will summarize both historic knowledge in the field as well as recently published data that has potential to shift current theories in how alphaviruses are able to function. This review is comprehensive, covering all parts of the alphaviral life cycle as well as a brief overview of their pathology and the current state of research in regards to vaccines and therapeutics for alphaviral disease.
Topics: Humans; Antiviral Agents; Virus Replication; Chikungunya virus; Alphavirus Infections; Caribbean Region
PubMed: 36436722
DOI: 10.1016/j.antiviral.2022.105476 -
Seminars in Cell & Developmental Biology Mar 2021Alphaviruses such as chikungunya and western equine encephalitis viruses are important human pathogens transmitted by mosquitoes that have recently caused large epidemic... (Review)
Review
Alphaviruses such as chikungunya and western equine encephalitis viruses are important human pathogens transmitted by mosquitoes that have recently caused large epidemic and epizootic outbreaks. The epidemic potential of alphaviruses is often related to enhanced mosquito transmission. Tissue barriers and antiviral responses impose bottlenecks to viral populations in mosquitoes. Substitutions in the envelope proteins and the presence of repeated sequence elements (RSEs) in the 3'UTR of epidemic viruses were proposed to be specifically associated to efficient replication in mosquito vectors. Here, we discuss the molecular mechanisms that originated RSEs, the evolutionary forces that shape the 3'UTR of alphaviruses, and the significance of RSEs for mosquito transmission. Finally, the presence of RSEs in the 3'UTR of viral genomes appears as evolutionary trait associated to mosquito adaptation and emerges as a common feature among viruses from the alphavirus and flavivirus genera.
Topics: 3' Untranslated Regions; Alphavirus Infections; Animals; Chikungunya virus; Culicidae; Encephalitis Virus, Western Equine; Flavivirus; Flavivirus Infections; Gene Expression Regulation; Genome, Viral; Humans; Microsatellite Repeats; Mosquito Vectors; Phylogeny; Signal Transduction; Viral Envelope Proteins; Virus Replication
PubMed: 32665176
DOI: 10.1016/j.semcdb.2020.07.006 -
Viruses Aug 2023Chikungunya virus (CHIKV), an alphavirus transmitted by mosquitoes, has experienced a recent re-emergence in various regions of the world, leading to large-scale...
Chikungunya virus (CHIKV), an alphavirus transmitted by mosquitoes, has experienced a recent re-emergence in various regions of the world, leading to large-scale outbreaks [...].
Topics: Animals; Chikungunya virus; Culicidae; Disease Outbreaks
PubMed: 37632110
DOI: 10.3390/v15081768 -
Cell Reports May 2023RNA interference (RNAi) is a well-established antiviral immunity. However, for mammalian somatic cells, antiviral RNAi becomes evident only when viral suppressors of...
RNA interference (RNAi) is a well-established antiviral immunity. However, for mammalian somatic cells, antiviral RNAi becomes evident only when viral suppressors of RNAi (VSRs) are disabled by mutations or VSR-targeting drugs, thereby limiting its scope as a mammalian immunity. We find that a wild-type alphavirus, Semliki Forest virus (SFV), triggers the Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs) in both mammalian somatic cells and adult mice. These SFV-vsiRNAs are located at a particular region within the 5' terminus of the SFV genome, Argonaute loaded, and active in conferring effective anti-SFV activity. Sindbis virus, another alphavirus, also induces vsiRNA production in mammalian somatic cells. Moreover, treatment with enoxacin, an RNAi enhancer, inhibits SFV replication dependent on RNAi response in vitro and in vivo and protects mice from SFV-induced neuropathogenesis and lethality. These findings show that alphaviruses trigger the production of active vsiRNA in mammalian somatic cells, highlighting the functional importance and therapeutic potential of antiviral RNAi in mammals.
Topics: Animals; Mice; RNA Interference; Antiviral Agents; Cell Line; RNA, Small Interfering; Semliki forest virus; Alphavirus Infections; Sindbis Virus; Mammals; Virus Replication
PubMed: 37104090
DOI: 10.1016/j.celrep.2023.112441 -
Nature Communications Jan 2024Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses....
Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses. However, based on studies with gene edited cells and knockout mice, blockade or abrogation of these receptors does not fully inhibit alphavirus infection, indicating the existence of additional uncharacterized entry factors. Here, we perform a CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells with a chimeric alphavirus expressing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candidate receptor. Expression of LDLR on the surface of neuronal or non-neuronal cells facilitates binding and infection of EEEV, Western equine encephalitis virus, and Semliki Forest virus. Domain mapping and binding studies reveal a low-affinity interaction with LA domain 3 (LA3) that can be enhanced by concatenation of LA3 repeats. Soluble decoy proteins with multiple LA3 repeats inhibit EEEV infection in cell culture and in mice. Our results establish LDLR as a low-affinity receptor for multiple alphaviruses and highlight a possible path for developing inhibitors that could mitigate infection and disease.
Topics: Horses; Animals; Mice; Alphavirus; Encephalitis Virus, Eastern Equine; Alphavirus Infections; Semliki forest virus; Lipoproteins, LDL
PubMed: 38172096
DOI: 10.1038/s41467-023-44624-x -
Cell Communication and Signaling : CCS Dec 2023Getah virus (GETV) was becoming more serious and posing a potential threat to animal safety and public health. Currently, there is limited comprehension regarding the...
Getah virus (GETV) was becoming more serious and posing a potential threat to animal safety and public health. Currently, there is limited comprehension regarding the pathogenesis and immune evasion mechanisms employed by GETV. Our study reveals that GETV infection exhibits the capacity for interferon antagonism. Specifically, the nonstructural protein nsP2 of GETV plays a crucial role in evading the host immune response. GETV nsP2 effectively inhibits the induction of IFN-β by blocking the phosphorylation and nuclear translocation of IRF3. Additionally, GETV nsP2 hinders the phosphorylation of STAT1 and its nuclear accumulation, leading to significantly impaired JAK-STAT signaling. Furthermore, the amino acids K648 and R649, situated in the C-terminal region of GETV nsP2, play a crucial role in facilitating nuclear localization. Not only do they affect the interference of nsP2 with the innate immune response, but they also exert an influence on the pathogenicity of GETV in mice. In summary, our study reveals novel mechanisms by which GETV evades the immune system, thereby offering a foundation for comprehending the pathogenic nature of GETV. Video Abstract.
Topics: Animals; Mice; Interferons; Alphavirus; Cell Line; Immunity, Innate; Immune Evasion
PubMed: 38110975
DOI: 10.1186/s12964-023-01392-x -
Viruses Jan 2022Alphaviruses () are arthropod-borne viruses responsible for several emerging diseases, maintained in nature through transmission between hematophagous arthropod vectors...
Alphaviruses () are arthropod-borne viruses responsible for several emerging diseases, maintained in nature through transmission between hematophagous arthropod vectors and susceptible vertebrate hosts. Although bats harbor many species of viruses, their role as reservoir hosts in emergent zoonoses has been verified only in a few cases. With bats being the second most diverse order of mammals, their implication in arbovirus infections needs to be elucidated. Reports on arbovirus infections in bats are scarce, especially in South American indigenous species. In this work, we report the genomic detection and identification of two different alphaviruses in oral swabs from bats captured in Northern Uruguay. Phylogenetic analysis identified Río Negro virus (RNV) in two different species: ( = 6) and spp. ( = 1) and eastern equine encephalitis virus (EEEV) in spp. ( = 2). Previous studies of our group identified RNV and EEEV in mosquitoes and horse serology, suggesting that they may be circulating in enzootic cycles in our country. Our findings reveal that bats can be infected by these arboviruses and that chiropterans could participate in the viral natural cycle as virus amplifiers or dead-end hosts. Further studies are warranted to elucidate the role of these mammals in the biological cycle of these alphaviruses in Uruguay.
Topics: Alphavirus; Alphavirus Infections; Animals; Arbovirus Infections; Arboviruses; Chiroptera; Encephalitis Virus, Eastern Equine; Phylogeny; Uruguay
PubMed: 35215862
DOI: 10.3390/v14020269 -
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 -
Viruses Feb 2023Alphaviruses are important human and animal pathogens that can cause a range of debilitating symptoms and are found worldwide. These include arthralgic diseases caused... (Review)
Review
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.
Topics: Animals; Humans; Alphavirus Infections; Alphavirus; Arthralgia; Encephalitis; RNA, Untranslated
PubMed: 36851776
DOI: 10.3390/v15020562 -
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