Chapter 25 : Innate Immune Responses Elicited by Reovirus and Rotavirus

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The mammalian orthoreoviruses (called simply reoviruses) are the type species of the genus, which also contains viruses that infect birds and reptiles. The reoviruses and rotaviruses are the subject of this chapter. The effect of NSP1 can be linked to its role as an antagonist of interferon (IFN) expression. Application of global approaches for identification of reovirus-induced IFN-stimulated genes (ISGs) should provide additional ISG candidates responsible for IFN’s effects on viral replication and possibly apoptosis induction. Recent reports point to NSP1 as the sole rotavirus gene product responsible for countering IFN-dependent innate immune responses. Rotavirus NSP1 is an antagonist of the IFN signaling pathway, most likely functioning through an E3 Ub ligase activity that induces the ubiquitination and proteasomal proteolysis of several members of the IRF family. Many viruses encode proteins that interfere with Jak-Stat signaling. However, there is no published evidence for similar disruption by reoviruses. Like analysis of strain-specific differences in IFN-β induction, genetic analyses using reassortant reoviruses identified the M1, L2, and S2 genes as determinants of strain-specific differences in sensitivity to the antiviral effects of IFN-β in cardiac myocytes.

Citation: Sherry B, Patton J, Dermody T. 2009. Innate Immune Responses Elicited by Reovirus and Rotavirus, p 403-422. 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.ch25
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Figure 1

Schematic diagram of signaling pathways activated by virus infection. Viral PAMPs such as single-stranded or double-stranded RNA activate numerous signaling cascades through TLR-dependent (e.g., TLR3, TLR7, and TLR9) and TLR-independent (MDA-5 and RIG-I) pathways, leading to kinase activation through TRAF family members. TRIF and MyD88 link TLRs to the TRAF proteins, whereas IPS-1 links MDA-5 and RIG-I to TRAF3. TRAF-dependent induction of the kinases JNK, IKK-α, IKK-β, IKK-ε, TBK1, and IRAK-1 induces the binding of ATF-2/c-Jun, IRF3, and NF-κB (p50 and p65) to the IFN-β promoter. (Modified from reference .)

Citation: Sherry B, Patton J, Dermody T. 2009. Innate Immune Responses Elicited by Reovirus and Rotavirus, p 403-422. 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.ch25
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Figure 2

Reovirus activation of IRF3 but not NF-κB requires RIG-I and IPS-1. (A) 293T cells were cotransfected with a control siRNA or an siRNA specific for RIG-I, MDA-5, or IPS-1, and with IRF3 reporter plasmid p-55C1BLuc and control plasmid p-Renilla-Luc. Following 24 h incubation, cells were infected with T3D at an MOI of 100 PFU/cell. Luciferase activity in cell culture lysates was determined at 24 h postinfection. (B) 293T cells were cotransfected with a control siRNA or an siRNA specific for either RIG-I or IPS-1, and with NF-κB reporter plasmid pNF-κB-Luc and p-RenillaLuc. Following 24 h incubation, cells were infected with T3D at an MOI of 100 PFU/cell. Luciferase activity in cell culture lysates was determined at 24 h postinfection. Results are presented as the ratio of normalized luciferase activity from infected cell lysates to that from mock-treated or mock-infected lysates for triplicate samples. For all panels, error bars indicate standard deviation. *, >0.05 as determined by Student’s test in comparison to mock treatment. (Modified from reference .)

Citation: Sherry B, Patton J, Dermody T. 2009. Innate Immune Responses Elicited by Reovirus and Rotavirus, p 403-422. 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.ch25
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Figure 3

The IFN-β response in cardiac myocyte cultures induced by reovirus strains T1L and T3D. Murine primary cardiac myocyte cultures were prepared from fetal mouse hearts. At 2 days post-plating, the cultures were infected at an MOI of 10 PFU/cell and harvested at 4 h postinfection. (A) Immunoblot of total cell lysates using the indicated antibodies (Stat1-P denotes phosphorylation on Tyr-701; Stat2-P denotes phosphorylation on Tyr-689). (B) Enzyme-linked immunosorbent assay quantitation of IFN-β in culture supernatants. (Figure courtesy of Jennifer Zurney, North Carolina State University.)

Citation: Sherry B, Patton J, Dermody T. 2009. Innate Immune Responses Elicited by Reovirus and Rotavirus, p 403-422. 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.ch25
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Figure 4

RING domain of rotavirus NSP1. (A) Schematic representation of structural and functional domains in the NSP1 protein of SA11 rotavirus. RING, RING finger; CytoLS, cytoplasm localization domain; RNA-BD, RNA-binding domain; αC19, recognition epitope of the C19 antibody used in detecting wild-type NSP1. (B) Organization of the consensus cysteine (C)- and histidine (H)-rich region of rotavirus NSP1 in comparison with the related domain of the SSM4 protein ( ) and the consensus plant homeodomain (PHD), viral C4HC3-type RING domain, and classic RING domain ( ). Residues coordinating binding of the two zinc atoms (Zn-1, Zn-2) of the PHD, vRING, and RING domains are indicated. X represents any amino acid. (C) Hypothetical organization of the RING domain of NSP1, including possible cross-bracing between the two zinc fingers. Note that the distances proposed between C6 and C7 and between C7 and C8 for NSP1 markedly differ from those of the PHD, vRING, and RING domains, suggesting that alternative organizations are possible.

Citation: Sherry B, Patton J, Dermody T. 2009. Innate Immune Responses Elicited by Reovirus and Rotavirus, p 403-422. 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.ch25
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Figure 5

Members of the IRF protein family targeted for degradation by rotavirus NSP1. (A) Structural and functional domains of the IRF3, IRF5, and IRF7 targets. DBD, tryptophan-pentad repeat DNA-binding domain; PRO, proline-rich region; IAD, IRF-interactive (dimerization) domain; ID, autoinhibitory domain; PEST, proline-glutamate-serine-threonine-rich domain; AD, constitutive activation domain; DWB, region similar to domain B in dwarfin family proteins; NLS, nuclear localization domain; NES, nuclear export signal; PRD, phosphorylation-mediated response domain ( ). (B) Immunoblot analysis of proteins transiently expressed in 293T cells showing that wild-type (wt) NSP1 induces the degradation of chimeric GFP-IRF3 protein and IRF7 ( ). (C) Immunoblot analysis showing that wild-type wtNSP1, but not the C-truncated form (NSP1ΔC17), induces degradation of IRF5 and IRF7 ( ).

Citation: Sherry B, Patton J, Dermody T. 2009. Innate Immune Responses Elicited by Reovirus and Rotavirus, p 403-422. 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.ch25
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