Chapter 22 : Togaviruses

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The family contains two genera, the genus and the genus. This chapter describes the interaction between the alphaviruses and the alpha/beta interferon (IFN-α/β) system, as relatively little research has been performed with rubella virus in this area, thwarted by the lack of a small-animal disease model. The alphaviruses are relatively uncomplicated, positivesense RNA viruses, encoding only seven proteins. The chapter reviews aspects of alphavirus infection and replication pertinent to virus virulence/attenuation and induction or evasion of the innate immune response. Although relatively simplistic, togavirus genome replication and RNA transcription are tightly and temporally regulated. Importantly, alphavirus RNA replication occurs not in the open cytoplasm but when associated with cytoplasmic surfaces of endosomal vesicles known as cytopathic vacuoles, modified from the intracellular membranes of infected host cells. Priming of TD-derived myeloid DCs (mDCs) with IFN-α/β induced residual antiviral activity against Sindbis virus (SINV) that appeared nearly as potent as that observed in cells from wild-type mice. A greater understanding of the interactions of togaviruses with the IFN-α/β system should lead to identification of pathogen vulnerabilities that can be exploited for antiviral drug and live-attenuated vaccine design.

Citation: Klimstra W, Ryman K. 2009. Togaviruses, p 353-372. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch22
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Figure 1

Diagrammatic representation of alphavirus replication in permissive cells. The replication cycle is depicted as a series of temporally regulated steps: ( ) translation and processing of nonstructural polyprotein; ( ) synthesis of complementary, negative-sense RNA; ( ) synthesis of progeny genomes; ( ) synthesis of subgenomic RNAs; ( ) translation and processing of structural polyprotein C/PE2/6KE1; ( ) packaging of progeny genomes into nucleocapsids; and ( ) envelopment of progeny virions at the plasma membrane.

Citation: Klimstra W, Ryman K. 2009. Togaviruses, p 353-372. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch22
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Figure 2

Induction of IFN-α/β as measured by a biological assay of supernatants collected from virus-infected (multiplicity of infection = 3) MEF cultures at different times postinfection. nc SINV is the Sindbis virus strain TR339 with the noncytopathic nsP2 726 G mutation ( ). wt SINV is the TR339 strain of Sindbis virus. SeV is a Sendai virus stock acquired from the American Type Culture Collection. Asterisks indicate times at which samples were not taken due to complete cytopathic effect. hpi, hours postinfection.

Citation: Klimstra W, Ryman K. 2009. Togaviruses, p 353-372. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch22
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Figure 3

Production of IFN-α/β measured by biological assay of serum after infection of CD-1 mice with similar doses (pfu or IU) of SINV (TR339 strain), EEEV, or VEEV virus or replicon particles. In EEEV-infected mice, IFN levels were below the limit of detection (*). hpi, hours postinfection.

Citation: Klimstra W, Ryman K. 2009. Togaviruses, p 353-372. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch22
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Figure 4

Relative sensitivity of the replication of SINV (TR339 strain), VEEV, or EEEV to IFN-α/β priming of Swiss 3T3 murine fibroblasts. Cells were treated with the indicated IFN concentration for 12 h prior to infection (multiplicity of infection = 3), and CPE was measured at 24 h postinfection.

Citation: Klimstra W, Ryman K. 2009. Togaviruses, p 353-372. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch22
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Figure 5

Diagrammatic representation of the PKR-mediated and PKR/RNase L/Mx-independent antiviral effects in SINV-infected primary DCs and mice in vivo. Constitutively expressed PKR significantly suppresses early virus replication; however, secreted IFN-α/β acts via an alternative pathway in the presence or absence of PKR, RNase L, and Mx to protect cells and clear virus infection. In the absence of the IFN-α/β-induced alternative pathway, virus replication continues unabated, resulting in cell death.

Citation: Klimstra W, Ryman K. 2009. Togaviruses, p 353-372. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch22
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Table 1

Disease-causing representatives of the family

Citation: Klimstra W, Ryman K. 2009. Togaviruses, p 353-372. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch22

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