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A structural and functional perspective of alphavirus replication and assembly.

ABSTRACT: Alphaviruses are small, spherical, enveloped, positive-sense ssRNA viruses responsible for a considerable number of human and animal diseases. Alphavirus members include Chikungunya virus, Sindbis virus, Semliki Forest virus, the western, eastern and Venezuelan equine encephalitis viruses, and the Ross River virus. Alphaviruses can cause arthritic diseases and encephalitis in humans and animals and continue to be a worldwide threat. The viruses are transmitted by blood-sucking arthropods, and replicate in both arthropod and vertebrate hosts. Alphaviruses form spherical particles (65-70 nm in diameter) with icosahedral symmetry and a triangulation number of four. The icosahedral structures of alphaviruses have been defined to very high resolutions by cryo-electron microscopy and crystallographic studies. In this review, we summarize the major events in alphavirus infection: entry, replication, assembly and budding. We focus on data acquired from structural and functional studies of the alphaviruses. These structural and functional data provide a broader perspective of the virus lifecycle and structure, and allow additional insight into these important viruses.

SUBMITTER: Jose J

PROVIDER: S-EPMC2762864 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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A structural and functional perspective of alphavirus replication and assembly.

Jose Joyce J Snyder Jonathan E JE Kuhn Richard J RJ

Future microbiology 20090901 7

Alphaviruses are small, spherical, enveloped, positive-sense ssRNA viruses responsible for a considerable number of human and animal diseases. Alphavirus members include Chikungunya virus, Sindbis virus, Semliki Forest virus, the western, eastern and Venezuelan equine encephalitis viruses, and the Ross River virus. Alphaviruses can cause arthritic diseases and encephalitis in humans and animals and continue to be a worldwide threat. The viruses are transmitted by blood-sucking arthropods, and re ...[more]

PMID: 19722838

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Project description:Alphaviruses are enveloped, positive-sense RNA viruses that are important causes of viral encephalomyelitis. Sindbis virus (SINV) infects the neurons of rodents and is a model for studying factors that regulate infection of neuronal cells. The outcome of alphavirus infection of the central nervous system is dependent on neuronal maturation status. Differentiated mature neurons survive and control viral replication better than undifferentiated immature neurons. The cellular factors involved in age-dependent susceptibility include higher levels of antiapoptotic and innate immune factors in mature neurons. Because NF-?B pathway activation is required for the initiation of both apoptosis and the host antiviral response, we analyzed the role of NF-?B during SINV infection of differentiated and undifferentiated rat neuronal cells. SINV infection induced canonical NF-?B activation, as evidenced by the degradation of I?B? and the phosphorylation and nuclear translocation of p65. Inhibition or deletion of the upstream I?B kinase substantially reduced SINV replication in differentiated but not in undifferentiated neuronal cells or mouse embryo fibroblasts. NF-?B inhibition did not affect the establishment of infection, replication complex formation, the synthesis of nonstructural proteins, or viral RNA synthesis in differentiated neurons. However, the translation of structural proteins was impaired, phosphorylation of the ? subunit of eukaryotic translation initiation factor 2 (eIF2?) was decreased, and host protein synthesis was maintained, suggesting that NF-?B activation was involved in the regulation of translation during infection of mature neurons. Inhibition or deletion of double-stranded RNA-activated protein kinase (PKR) also decreased eIF2? phosphorylation, the translation of viral structural proteins, and virus production. Therefore, canonical NF-?B activation synergizes with PKR to promote SINV replication in differentiated neurons by facilitating viral structural protein translation.IMPORTANCE Mosquito-borne alphaviruses are a significant and growing cause of viral encephalomyelitis worldwide. The outcome of alphaviral neuronal infections is host age dependent and greatly affected by neuronal maturation status, with differentiated, mature neurons being more resistant to infection than undifferentiated, immature neurons. The biological factors that change during neuronal maturation and that influence the outcome of viral infection are currently only partially defined. These studies investigated the role of NF-?B in determining the outcome of alphaviral infection in mature and immature neurons. Inhibition of canonical NF-?B activation decreased alphavirus replication in mature neurons by regulating protein synthesis and limiting the production of the viral structural proteins but had little effect on viral replication in immature neurons or fibroblasts. Therefore, NF-?B is a signaling pathway that influences the maturation-dependent outcome of alphaviral infection in neurons and that highlights the importance of cellular context in determining the effects of signal pathway activation.

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A structural and functional perspective of alphavirus replication and assembly.

Publications

A structural and functional perspective of alphavirus replication and assembly.

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