O'nyong nyong Virus Molecular Determinants of Unique Vector Specificity Reside in Non-Structural Protein 3

Saxton-Shaw, Kali D.; Ledermann, Jeremy P.; Borland, Erin M.; Stovall, Janae L.; Mossel, Eric C.; Singh, Amber; Wilusz, Jeffrey; Powers, Ann M.

doi:10.1371/journal.pntd.0001931

Cited by 59 publications

(72 citation statements)

References 38 publications

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“…Viable nsP chimeras have been generated for two closely related members of Semliki Forest complex, Chikungunya and O'nyongnyong viruses; however, nsP chimeras between members of different alphavirus complexes have not been reported, presumably due to nsP incompatibilities (71). Taken together, our data suggest that the electroporation of capped, genomic RNA of EILVeRFP, EILV-eRFP with SINV structural ORF, or 3= UTR chimeras can initiate the virus replication cycle by the translation of the nsP ORF.…”

Section: Fig 8 Predicted Secondary Structure Of Eilv (A) and Sinv (B) 3=mentioning

confidence: 80%

Eilat Virus Host Range Restriction Is Present at Multiple Levels of the Virus Life Cycle

Nasar

Gorchakov

Tesh

et al. 2015

J Virol

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Most 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. IMPORTANCE Our 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.A rthropod-borne viruses (arboviruses) such as dengue virus, Chikungunya virus, West Nile virus, and Rift Valley fever virus are important causes of human and animal disease worldwide (1, 2). Arboviruses encompass diverse virus families, including Togaviridae, Bunyaviridae, Flaviviridae, Rhabdoviridae, Orthomyxoviridae, Reoviridae, and Asfarviridae, and are maintained in nature primarily through biological transmission between susceptible vertebrate hosts and hematophagous arthropods such as ticks, mosquitoes, and other biting flies (1, 2). This ability to infect diverse vertebrate and arthropod hosts enables arboviruses to persist in nature; however, the viral factors that facilitate their broad host ...

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Section: Fig 8 Predicted Secondary Structure Of Eilv (A) and Sinv (B) 3=mentioning

confidence: 80%

Eilat Virus Host Range Restriction Is Present at Multiple Levels of the Virus Life Cycle

Nasar

Gorchakov

Tesh

et al. 2015

J Virol

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“…Due to its rapid evolution, the HVD is hypothesized to be involved in the optimization of replication in diverse host cell types (51). Chimeric viruses containing CHIKV and o'nyong-nyong virus (ONNV) genes showed that, in the CHIKV backbone, the ONNV nsP3 gene confers the ability to infect Anopheles mosquitoes, natural vectors of this close relative of CHIKV (52). Another study suggested that deletion of the HVD of Sindbis virus causes it to be defective for mosquito cell infection (53).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Genome Scale Phylogenetic Study Provides New Insights on the Global Expansion of Chikungunya Virus

Chen

Puri

Fedorova

et al. 2016

J Virol

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Since the India and Indian Ocean outbreaks of 2005 and 2006, the global distribution of chikungunya virus (CHIKV) and the locations of epidemics have dramatically shifted. First, the Indian Ocean lineage (IOL) caused sustained epidemics in India and has radiated to many other countries. Second, the Asian lineage has caused frequent outbreaks in the Pacific islands and in 2013 was introduced into the Caribbean, followed by rapid spread to nearly all of the neotropics. Further, CHIKV epidemics, as well as exported cases, have been reported in central Africa after a long period of perceived silence. To understand these changes and to anticipate the future of the virus, the exact distribution, genetic diversity, transmission routes, and future epidemic potential of CHIKV require further assessment. To do so, we conducted the most comprehensive phylogenetic analysis to date, examined CHIKV evolution and transmission, and explored distinct genetic factors associated with the emergence of the East/Central/ South African (ECSA) lineage, the IOL, and the Asian lineage. Our results reveal contrasting evolutionary patterns among the lineages, with growing genetic diversities observed in each, and suggest that CHIKV will continue to be a major public health threat with the potential for further emergence and spread. IMPORTANCE Chikungunya fever is a reemerging infectious disease that is transmitted by

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“…Construction of the chimeras receiving material not bordered by these sites and the point chimeras was based on a strategy using type IIs restriction enzymes adapted from Blakqori and Weber [12] and is outlined in detail by Saxton-Shaw et al for the generation chikungunya/o′nyong nyong chimeric viruses [13]. This method allowed the generation of chimeras and point mutants without the introduction of nonnative nucleotides to the virus.…”

Section: Methodsmentioning

confidence: 99%

Molecular Determinants of Mouse Neurovirulence and Mosquito Infection for Western Equine Encephalitis Virus

et al. 2013

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Western equine encephalitis virus (WEEV) is a naturally occurring recombinant virus derived from ancestral Sindbis and Eastern equine encephalitis viruses. We previously showed that infection by WEEV isolates McMillan (McM) and IMP-181 (IMP) results in high (∼90–100%) and low (0%) mortality, respectively, in outbred CD-1 mice when virus is delivered by either subcutaneous or aerosol routes. However, relatively little is known about specific virulence determinants of WEEV. We previously observed that IMP infected Culex tarsalis mosquitoes at a high rate (app. 80%) following ingestion of an infected bloodmeal but these mosquitoes were infected by McM at a much lower rate (10%). To understand the viral role in these phenotypic differences, we characterized the pathogenic phenotypes of McM/IMP chimeras. Chimeras encoding the E2 of McM on an IMP backbone (or the reciprocal) had the most significant effect on infection phenotypes in mice or mosquitoes. Furthermore, exchanging the arginine, present on IMP E2 glycoprotein at position 214, for the glutamine present at the same position on McM, ablated mouse mortality. Curiously, the reciprocal exchange did not confer mouse virulence to the IMP virus. Mosquito infectivity was also determined and significantly, one of the important loci was the same as the mouse virulence determinant identified above. Replacing either IMP E2 amino acid 181 or 214 with the corresponding McM amino acid lowered mosquito infection rates to McM-like levels. As with the mouse neurovirulence, reciprocal exchange of amino acids did not confer mosquito infectivity. The identification of WEEV E2 amino acid 214 as necessary for both IMP mosquito infectivity and McM mouse virulence indicates that they are mutually exclusive phenotypes and suggests an explanation for the lack of human or equine WEE cases even in the presence of active transmission.

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O'nyong nyong Virus Molecular Determinants of Unique Vector Specificity Reside in Non-Structural Protein 3

Cited by 59 publications

References 38 publications

Eilat Virus Host Range Restriction Is Present at Multiple Levels of the Virus Life Cycle

Eilat Virus Host Range Restriction Is Present at Multiple Levels of the Virus Life Cycle

Comprehensive Genome Scale Phylogenetic Study Provides New Insights on the Global Expansion of Chikungunya Virus

Molecular Determinants of Mouse Neurovirulence and Mosquito Infection for Western Equine Encephalitis Virus

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