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Nature Communications Jan 2024Alphaviruses are arboviruses transmitted by mosquitoes and are pathogenic to humans and livestock, causing a substantial public health burden. So far, several receptors...
Alphaviruses are arboviruses transmitted by mosquitoes and are pathogenic to humans and livestock, causing a substantial public health burden. So far, several receptors have been identified for alphavirus entry; however, they cannot explain the broad host range and tissue tropism of certain alphaviruses, such as Getah virus (GETV), indicating the existence of additional receptors. Here we identify the evolutionarily conserved low-density lipoprotein receptor (LDLR) as a new cell entry factor for GETV, Semliki Forest virus (SFV), Ross River virus (RRV) and Bebaru virus (BEBV). Ectopic expression of LDLR facilitates cellular binding and internalization of GETV, which is mediated by the interaction between the E2-E1 spike of GETV and the ligand-binding domain (LBD) of LDLR. Antibodies against LBD block GETV infection in cultured cells. In addition, the GST-LBD fusion protein inhibits GETV infection both in vitro and in vivo. Notably, we identify the key amino acids in LDLR-LBD that played a crucial role in viral entry; specific mutations in the CR4 and CR5 domain of LDLR-LBD reduce viral entry to cells by more than 20-fold. These findings suggest that targeting the LDLR-LBD could be a potential strategy for the development of antivirals against multiple alphaviruses.
Topics: Animals; Humans; Alphavirus; Virus Internalization; Semliki forest virus; Alphavirus Infections; Culicidae
PubMed: 38245515
DOI: 10.1038/s41467-024-44872-5 -
Viruses Dec 2020Enveloped 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... (Review)
Review
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.
Topics: Alphavirus; Alphavirus Infections; Animals; Cell Membrane; Cholesterol; Host-Pathogen Interactions; Humans; Lipid Metabolism; Viral Envelope; Virus Internalization; Virus Release; Virus Replication
PubMed: 33383613
DOI: 10.3390/v13010035 -
Cell Jun 1995
Review
Topics: Alphavirus; Flavivirus; Membrane Glycoproteins; Viral Fusion Proteins
PubMed: 7774004
DOI: 10.1016/0092-8674(95)90523-5 -
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 -
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 -
The Journal of Infectious Diseases Dec 2016Chikungunya virus (CHIKV) is a reemerging alphavirus that causes acute febrile illness and severe joint pain in humans. Although acute symptoms often resolve within a... (Review)
Review
Chikungunya virus (CHIKV) is a reemerging alphavirus that causes acute febrile illness and severe joint pain in humans. Although acute symptoms often resolve within a few days, chronic joint and muscle pain can be long lasting. In the last decade, CHIKV has caused widespread outbreaks of unprecedented scale in the Americas, Asia, and the Indian Ocean island regions. Despite these outbreaks and the continued expansion of CHIKV into new areas, mechanisms of chikungunya pathogenesis and disease are not well understood. Experimental animal models are indispensable to the field of CHIKV research. The most commonly used experimental animal models of CHIKV infection are mice and nonhuman primates; each model has its advantages for studying different aspects of CHIKV disease. This review will provide an overview of animal models used to study CHIKV infection and disease and major advances in our understanding of chikungunya obtained from studies performed in these models.
Topics: Animals; Chikungunya Fever; Chikungunya virus; Disease Models, Animal; Mice; Primates
PubMed: 27920178
DOI: 10.1093/infdis/jiw284 -
Journal of Virology Nov 2023Alphavirus replicons are being developed as self-amplifying RNAs aimed at improving the efficacy of mRNA vaccines. These replicons are convenient for genetic...
Alphavirus replicons are being developed as self-amplifying RNAs aimed at improving the efficacy of mRNA vaccines. These replicons are convenient for genetic manipulations and can express heterologous genetic information more efficiently and for a longer time than standard mRNAs. However, replicons mimic many aspects of viral replication in terms of induction of innate immune response, modification of cellular transcription and translation, and expression of nonstructural viral genes. Moreover, all replicons used in this study demonstrated expression of heterologous genes in cell- and replicon's origin-specific modes. Thus, many aspects of the interactions between replicons and the host remain insufficiently investigated, and further studies are needed to understand the biology of the replicons and their applicability for designing a new generation of mRNA vaccines. On the other hand, our data show that replicons are very flexible expression systems, and additional modifications may have strong positive impacts on protein expression.
Topics: Alphavirus; mRNA Vaccines; Replicon; Virus Replication; RNA, Viral; Host Microbial Interactions; Viral Proteins; Gene Expression Regulation, Viral
PubMed: 37877718
DOI: 10.1128/jvi.01225-23 -
Viruses Feb 2018Alphaviruses are arthropod-borne viruses and are predominantly transmitted via mosquito vectors. This vector preference by alphaviruses raises the important question of... (Review)
Review
Alphaviruses are arthropod-borne viruses and are predominantly transmitted via mosquito vectors. This vector preference by alphaviruses raises the important question of the determinants that contribute to vector competence. There are several tissue barriers of the mosquito that the virus must overcome in order to establish a productive infection. Of importance are the midgut, basal lamina and the salivary glands. Infection of the salivary glands is crucial for virus transmission during the mosquito's subsequent bloodfeed. Other factors that may contribute to vector competence include the microflora and parasites present in the mosquito, environmental conditions, the molecular determinants of the virus to adapt to the vector, as well as the effect of co-infection with other viruses. Though mosquito innate immunity is a contributing factor to vector competence, it will not be discussed in this review. Detailed understanding of these factors will be instrumental in minimising transmission of alphaviral diseases.
Topics: Alphavirus; Alphavirus Infections; Animals; Coinfection; Culicidae; Humans; Mosquito Vectors; Mutation; RNA, Viral
PubMed: 29443908
DOI: 10.3390/v10020084 -
Journal of Virology Nov 2023Our study highlights the mechanisms behind the cell's resistance to stress granule (SG) formation after infection with Old World alphaviruses. Shortly after infection,...
Our study highlights the mechanisms behind the cell's resistance to stress granule (SG) formation after infection with Old World alphaviruses. Shortly after infection, the replication of these viruses hinders the cell's ability to form SGs, even when exposed to chemical inducers such as sodium arsenite. This resistance is primarily attributed to virus-induced transcriptional and translational shutoffs, rather than interactions between the viral nsP3 and the key components of SGs, G3BP1/2, or the ADP-ribosylhydrolase activity of nsP3 macro domain. While interactions between G3BPs and nsP3 are essential for the formation of viral replication complexes, their role in regulating SG development appears to be small, if any. Cells harboring replicating viruses or replicons with lower abilities to inhibit transcription and/or translation, but expressing wild-type nsP3, retain the ability for SG development. Understanding these mechanisms of regulation of SG formation contributes to our knowledge of viral replication and the intricate relationships between alphaviruses and host cells.
Topics: Alphavirus; DNA Helicases; Host Microbial Interactions; Poly-ADP-Ribose Binding Proteins; Protein Biosynthesis; Replicon; RNA Helicases; RNA Recognition Motif Proteins; Stress Granules; Transcription, Genetic; Viral Nonstructural Proteins; Virus Replication
PubMed: 37902397
DOI: 10.1128/jvi.00979-23 -
Viruses Aug 2022Mayaro virus is an emerging arbovirus that causes nonspecific febrile illness or arthralgia syndromes similar to the Chikungunya virus, a virus closely related from the... (Review)
Review
Mayaro virus is an emerging arbovirus that causes nonspecific febrile illness or arthralgia syndromes similar to the Chikungunya virus, a virus closely related from the family. MAYV outbreaks occur more frequently in the northern and central-western states of Brazil; however, in recent years, virus circulation has been spreading to other regions. Due to the undifferentiated initial clinical symptoms between MAYV and other endemic pathogenic arboviruses with geographic overlapping, identification of patients infected by MAYV might be underreported. Additionally, the lack of specific prophylactic approaches or antiviral drugs limits the pharmacological management of patients to treat symptoms like pain and inflammation, as is the case with most pathogenic alphaviruses. In this context, this review aims to present the state-of-the-art regarding the screening and development of compounds/molecules which may present anti-MAYV activity and infection inhibition.
Topics: Alphavirus; Alphavirus Infections; Antiviral Agents; Arboviruses; Chikungunya virus; Drug Development; Humans
PubMed: 36016409
DOI: 10.3390/v14081787