Rotavirus Antagonizes Cellular Antiviral Responses by Inhibiting the Nuclear Accumulation of STAT1, STAT2, and NF-κB

Holloway, Gavan; Truong, Thanhmai T.; Coulson, Barbara S.

doi:10.1128/jvi.01450-08

Cited by 86 publications

(114 citation statements)

References 48 publications

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“…Adenovirus E1A protein inhibits TNF-a-induced NF-kB activation through suppression of IKK activity and IkBa phosphorylation (36). Rotavirus NSP1 inhibits NF-kB activation by inducing proteasomedependent degradation of b-transducin repeat-containing protein (37,38). In the current study, we report that EV71 2C protein can directly interact with IKKb by inhibiting IKKb activation and IkBa phosphorylation/degradation, and thus inhibits TNF-ainduced NF-kB activation.…”

Section: Discussionsupporting

confidence: 49%

Enterovirus 71 2C Protein Inhibits TNF-α–Mediated Activation of NF-κB by Suppressing IκB Kinase β Phosphorylation

Zheng

Zhang

et al. 2011

The Journal of Immunology

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Enterovirus 71 (EV71), a single, positive-stranded RNA virus, has been regarded as the most important neurotropic enterovirus after the eradication of the poliovirus. EV71 infection can cause hand, foot, and mouth disease or herpangina. Cytokine storm with elevated levels of proinflammatory and inflammatory cytokines, including TNF-α, has been proposed to explain the pathogenesis of EV71-induced disease. TNF-α–mediated NF-κB signaling pathway plays a key role in inflammatory response. We hypothesized that EV71 might also moderate host inflammation by interfering with this pathway. In this study, we tested this hypothesis and identified EV71 2C protein as an antagonist of TNF-α–mediated activation of NF-κB signaling pathway. Expression of 2C protein significantly reduced TNF-α–mediated NF-κB activation in 293T cells as measured by gene reporter and gel mobility shift assays. Furthermore, overexpression of TNFR-associated factor 2-, MEK kinase 1-, IκB kinase (IKK)α-, or IKKβ-induced NF-κB activation, but not constitutively active mutant of IKKβ (IKKβ SS/EE)-induced NF-κB activation, was inhibited by 2C protein. These data together suggested that the activation of IKKβ is most likely targeted by 2C; this notion was further strengthened by immunoblot detection of IKKβ phosphorylation and IκBα phosphorylation and degradation. Coimmunoprecipitation and colocalization of 2C and IKKβ expressed in mammalian cells provided compelling evidence that 2C interacts with IKKβ. Collectively, our data indicate that EV71 2C protein inhibits IKKβ activation and thus blocks NF-κB activation.

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Section: Discussionsupporting

confidence: 49%

Enterovirus 71 2C Protein Inhibits TNF-α–Mediated Activation of NF-κB by Suppressing IκB Kinase β Phosphorylation

Zheng

Zhang

et al. 2011

The Journal of Immunology

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“…5) compared to that of cytokine secretion in BCR-stimulated mockinfected CBC. Both the low level of production of cytokines generated by RV alone and the inhibition of BCR-induced cytokine production could be explained by an RV-dependent blockage of the nuclear accumulation of NF-B in infected cells (a critical transcription factor in B cells for the expression of some proinflammatory cytokines genes, including IL-6 and IL-8 [3]), as has been shown recently for RV (29,38).…”

Section: Discussionmentioning

confidence: 67%

Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin

Narváez

Franco

Ángel

et al. 2010

J Virol

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Rotaviruses (RV) are the main cause of severe gastroenteritis in infants and are responsible for the death of approximately 600,000 young children annually around the world (54 and http://www.who.int/immunization monitoring/burden/rotavirus estimates/en/). At present, two live attenuated vaccines are licensed for use in humans, and both vaccines are highly protective against severe disease in developed countries (60,69). However, these oral vaccines induce lower levels of protection in children from developing countries, suggesting that the improvement of these vaccine or the development of new RV vaccines is warranted (32). Although the RV immune response has been extensively studied in both animals and humans, the immune factors that correlate with protection for natural infection or vaccination in people remain unclear, and this is an important obstacle for the development of the next generation of RV vaccines (2, 25).B cells play a critical role in the RV immune response, and both intestinal and systemic immunoglobulins (Ig) are associated with protection (25). For example, in the murine model, B-cell-but not T-cell-deficient mice are unable to establish long-lasting protective immunity against RV reinfection (26). The interaction of RV with B cells has been shown to be peculiar in many ways: the structural viral protein VP6 binds to an important fraction of human naive B cells via surface Ig (55, 58), and VP6 memory B cells (mBC) are enriched in the CD27 Ϫ IgG ϩ (58) and CD27 ϩ IgM ϩ subsets (66). VP6-specific naive B cells and, to a lesser extent, the mBC predominantly use the VH1-46 gene segment (66). Moreover, a massive Tcell-independent B cell activation and humoral response can be detected in vivo after oral RV infection in mice (10). However, the activation of these cells is probably viral strain dependent, since simian rhesus RV (RRV), but not bovine WC3 RV, has been shown to polyclonally stimulate a total antibodysecreting cell (ASC) response in intestinal organ fragment cultures (44). Although the principal immune function of B cells has been associated with the production of Ig, recent reports show that these cells also can play an important role in modulating the immune response independently of Ig through the production of cytokines like tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL-6), and IL-10 and their related potential function as antigen-presenting cells (3,18,31,67).We and others have shown that RVs undergo systemic, extraintestinal replication in both immunodeficient and wild-type mice (16,24). In addition, a significant antigenemia and viremia is seen in most acutely infected children (8, 9). In particular, we have shown the in vivo replication of homologous and heterologous RV strains in B220 ϩ cells (a marker expressed by B cells or plasmacytoid dendritic cells [pDC]) obtained from murine mesenteric lymph node (24), and recently we also demonstrated that approximately 10% of primary human circulating B cells (CBC) are targets of RV infection in vitro (49).

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“…3C), suggesting that inhibition of IFN-mediated STAT1 phosphorylation is most effective at later times during infection. It was previously reported that at 6 hpi, RV-infected cells prevent STAT1 and STAT2 nuclear localization following exogenous IFN stimulation (30). Thus, in addition to the induction and release of exogenous IFN, at 6 hpi, RV may interfere with STAT1 function by blocking its nuclear localization, a step that occurs subsequent to Y701 activation.…”

Section: Discussionmentioning

confidence: 92%

“…Regardless of their ability to regulate IFN secretion later during infection, rotavirus infection likely triggers a conserved signaling pathway early in infection, resulting in activation of IRF3, NF-B-dependent VSIGs, and possibly IFN itself (26). We and others have found that early during infection, both RRV and UK RVs activate the cytosolic PRRs RIG-I and MDA-5 in a replication-dependent manner, and subsequent signaling mediated through the mitochondrial adaptor MAVS results in induction of several IRF3-and NF-B-dependent VSIGs and IFNs (20,23,(27)(28)(29)(30)(31)(32)(33). However, at later times during infection (16 to 24 h postinfection [hpi]), RRV more effectively prevents IFN secretion than UK RV.…”

mentioning

confidence: 98%

“…The NSP1 protein of still other RV strains may inhibit IFN induction by interacting with beta transducin repeat-containing protein (␤-TrCP), but without causing its degradation, in a manner reminiscent of the A49 protein of vaccinia virus (34; M. Morelli and J. T. Patton, personal communication). In addition, certain rotaviruses sequester the NF-B p65 subunit in viroplasms during infection (30), potentially blocking NF-B signals in a ␤-TrCP-independent manner. Although the viral factors and mechanisms used in ␤-TrCP degradation-independent inhibition of NF-B transcriptional activity have yet to be determined, it is likely that rotavirus inhibition of NF-B-dependent innate signaling is critical for inhibition of the innate immune response in murine villous intestinal epithelial cells (IECs) in vivo (20).…”

mentioning

confidence: 99%

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Rotavirus NSP1 Protein Inhibits Interferon-Mediated STAT1 Activation

Rott

Phan

et al. 2014

J Virol

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Rotavirus Antagonizes Cellular Antiviral Responses by Inhibiting the Nuclear Accumulation of STAT1, STAT2, and NF-κB

Cited by 86 publications

References 48 publications

Enterovirus 71 2C Protein Inhibits TNF-α–Mediated Activation of NF-κB by Suppressing IκB Kinase β Phosphorylation

Enterovirus 71 2C Protein Inhibits TNF-α–Mediated Activation of NF-κB by Suppressing IκB Kinase β Phosphorylation

Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin

Rotavirus NSP1 Protein Inhibits Interferon-Mediated STAT1 Activation

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