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Insect-specific flaviviruses: a systematic review of their discovery, host range, mode of transmission, superinfection exclusion potential and genomic organization.

ABSTRACT: There has been a dramatic increase in the number of insect-specific flaviviruses (ISFs) discovered in the last decade. Historically, these viruses have generated limited interest due to their inability to infect vertebrate cells. This viewpoint has changed in recent years because some ISFs have been shown to enhance or suppress the replication of medically important flaviviruses in co-infected mosquito cells. Additionally, comparative studies between ISFs and medically important flaviviruses can provide a unique perspective as to why some flaviviruses possess the ability to infect and cause devastating disease in humans while others do not. ISFs have been isolated exclusively from mosquitoes in nature but the detection of ISF-like sequences in sandflies and chironomids indicates that they may also infect other dipterans. ISFs can be divided into two distinct phylogenetic groups. The first group currently consists of approximately 12 viruses and includes cell fusing agent virus, Kamiti River virus and Culex flavivirus. These viruses are phylogenetically distinct from all other known flaviviruses. The second group, which is apparently not monophyletic, currently consists of nine viruses and includes Chaoyang virus, Nounané virus and Lammi virus. These viruses phylogenetically affiliate with mosquito/vertebrate flaviviruses despite their apparent insect-restricted phenotype. This article provides a review of the discovery, host range, mode of transmission, superinfection exclusion ability and genomic organization of ISFs. This article also attempts to clarify the ISF nomenclature because some of these viruses have been assigned more than one name due to their simultaneous discoveries by independent research groups.

SUBMITTER: Blitvich BJ

PROVIDER: S-EPMC4411683 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Insect-specific flaviviruses: a systematic review of their discovery, host range, mode of transmission, superinfection exclusion potential and genomic organization.

Blitvich Bradley J BJ Firth Andrew E AE

Viruses 20150410 4

There has been a dramatic increase in the number of insect-specific flaviviruses (ISFs) discovered in the last decade. Historically, these viruses have generated limited interest due to their inability to infect vertebrate cells. This viewpoint has changed in recent years because some ISFs have been shown to enhance or suppress the replication of medically important flaviviruses in co-infected mosquito cells. Additionally, comparative studies between ISFs and medically important flaviviruses can ...[more]

PMID: 25866904

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Project description:The genus Flavivirus contains emerging arthropod-borne viruses (arboviruses) infecting vertebrates, as well as insect-specific viruses (ISVs) (i.e., viruses whose host range is restricted to insects). ISVs are evolutionary precursors to arboviruses. Knowledge of the nature of the ISV infection block in vertebrates could identify functions necessary for the expansion of the host range toward vertebrates. Mapping of host restrictions by complementation of ISV and arbovirus genome functions could generate knowledge critical to predicting arbovirus emergence. Here we isolated a novel flavivirus, termed Niénokoué virus (NIEV), from mosquitoes sampled in Côte d'Ivoire. NIEV groups with insect-specific flaviviruses (ISFs) in phylogeny and grows in insect cells but not in vertebrate cells. We generated an infectious NIEV cDNA clone and a NIEV reporter replicon to study growth restrictions of NIEV in comparison to yellow fever virus (YFV), for which the same tools are available. Efficient RNA replication of the NIEV reporter replicon was observed in insect cells but not in vertebrate cells. Initial translation of the input replicon RNA in vertebrate cells was functional, but RNA replication did not occur. Chimeric YFV carrying the envelope proteins of NIEV was recovered via electroporation in C6/36 insect cells but did not infect vertebrate cells, indicating a block at the level of entry. Since the YF/NIEV chimera readily produced infectious particles in insect cells but not in vertebrate cells despite efficient RNA replication, restriction is also determined at the level of assembly/release. Taking the results together, the ability of ISF to infect vertebrates is blocked at several levels, including attachment/entry and RNA replication as well as assembly/release. IMPORTANCE Most viruses of the genus Flavivirus, e.g., YFV and dengue virus, are mosquito borne and transmitted to vertebrates during blood feeding of mosquitoes. Within the last decade, an increasing number of viruses with a host range exclusively restricted to insects in close relationship to the vertebrate-pathogenic flaviviruses were discovered in mosquitoes. To identify barriers that could block the arboviral vertebrate tropism, we set out to identify the steps at which the ISF replication cycle fails in vertebrates. Our studies revealed blocks at several levels, suggesting that flavivirus host range expansion from insects to vertebrates was a complex process that involved overcoming multiple barriers.

Project description:UnlabelledMany viruses have the capacity to prevent a cell from being infected by a second virus, often termed superinfection exclusion. Alphaherpesviruses, including the human pathogen herpes simplex virus 1 (HSV-1) and the animal herpesvirus pseudorabies virus (PRV), encode a membrane-bound glycoprotein, gD, that can interfere with subsequent virion entry. We sought to characterize the timing and mechanism of superinfection exclusion during HSV-1 and PRV infection. To this end, we utilized recombinant viruses expressing fluorescent protein (FP) markers of infection that allowed the visualization of viral infections by microscopy and flow cytometry as well as the differentiation of viral progeny. Our results demonstrated the majority of HSV-1- and PRV-infected cells establish superinfection exclusion by 2 h postinfection. The modification of viral infections by virion inactivation and phosphonoacetic acid, cycloheximide, and actinomycin D treatments indicated new protein synthesis is needed to establish superinfection exclusion. Primary infection with gene deletion PRV recombinants identified that new gD expression is not required to establish superinfection exclusion of a secondary viral inoculum. We also identified the timing of coinfection events during axon-to-cell spread, with most occurring within a 2-h window, suggesting a role for cellular superinfection exclusion during neuroinvasive spread of infection. In summary, we have characterized a gD-independent mechanism of superinfection exclusion established by two members of the alphaherpesvirus family and identified a potential role of exclusion during the pathogenic spread of infection.ImportanceSuperinfection exclusion is a widely observed phenomenon initiated by a primary viral infection to prevent further viruses from infecting the same cell. The capacity for alphaherpesviruses to infect the same cell impacts rates of interviral recombination and disease. Interviral recombination allows genome diversification, facilitating the development of resistance to antiviral therapeutics and evasion of vaccine-mediated immune responses. Our results demonstrate superinfection exclusion occurs early, through a gD-independent process, and is important in the directed spread of infection. Identifying when and where in an infected host viral genomes are more likely to coinfect the same cell and generate viral recombinants will enhance the development of effective antiviral therapies and interventions.

Project description:Superinfection exclusion is a widespread phenomenon that prevents secondary infections by closely related viruses. The vaccinia virus A56 and K2 proteins in the cell membrane can prevent superinfection by interacting with the entry-fusion complex of subsequent viruses. Here, we described another form of exclusion that is established earlier in infection and does not require the A56 or K2 protein. Cells infected with one or more infectious virions excluded hundreds of superinfecting vaccinia virus particles. A related orthopoxvirus, but neither a flavivirus nor a rhabdovirus, was also excluded, indicating selectivity. Although superinfecting vaccinia virus bound to cells, infection was inhibited at the membrane fusion step, thereby preventing core entry into the cytoplasm and early gene expression. In contrast, A56/K2 protein-mediated exclusion occurred subsequent to membrane fusion. Induction of resistance to superinfection depended on viral RNA and protein synthesis by the primary virus but did not require DNA replication. Although superinfection resistance correlated with virus-induced changes in the cytoskeleton, studies with mutant vaccinia viruses indicated that the cytoskeletal changes were not necessary for resistance to superinfection. Interferon-inducible transmembrane proteins, which can inhibit membrane fusion in other viral systems, did not prevent vaccinia virus membrane fusion, suggesting that these interferon-inducible proteins are not involved in superinfection exclusion. While the mechanism remains to be determined, the early establishment of superinfection exclusion may provide a "winner-take-all" reward to the first poxvirus particles that successfully initiate infection and prevent the entry and genome reproduction of defective or less fit particles.The replication of a virus usually follows a defined sequence of events: attachment, entry into the cytoplasm or nucleus, gene expression, genome replication, assembly of infectious particles, and spread to other cells. Although multiple virus particles may enter a cell at the same time, mechanisms exist to prevent infection by subsequent viruses. The latter phenomenon, known as superinfection exclusion, can occur by a variety of mechanisms that are not well understood. We showed that superinfection by vaccinia virus was prevented at the membrane fusion step, which closely followed virion attachment. Thus, neither gene expression nor genome replication of the superinfecting virus occurred. Expression of early proteins by the primary virus was necessary and sufficient to induce the superinfection-resistant state. Superinfection exclusion may be beneficial to vaccinia virus by selecting particles that can infect cells rapidly, excluding defective particles and synchronizing the replication cycle.

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Insect-specific flaviviruses: a systematic review of their discovery, host range, mode of transmission, superinfection exclusion potential and genomic organization.

Publications

Insect-specific flaviviruses: a systematic review of their discovery, host range, mode of transmission, superinfection exclusion potential and genomic organization.

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