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Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response.

ABSTRACT: We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells--which are associated with enhanced RSV disease--and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease.

SUBMITTER: Munir S

PROVIDER: S-EPMC3080852 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response.

Munir Shirin S Hillyer Philippa P Le Nouën Cyril C Buchholz Ursula J UJ Rabin Ronald L RL Collins Peter L PL Bukreyev Alexander A

PLoS pathogens 20110421 4

We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autolo ...[more]

PMID: 21533073

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Project description:Respiratory syncytial virus (RSV) is a frequent cause of respiratory illness among pediatric and elderly populations. The severity of the respiratory disease is determined, in part, by RSV virulence and the host immune response, especially type I interferon (IFN) production. Using proteomics for the identification of partner proteins associated with RSV-encoded matrix (M) protein in transiently M-expressed and RSV-infected cells, we identified many M-interacting proteins involved in diverse biological processes including cell stress and innate immune response, highlighting M protein as a novel antagonist of IFN-β potentially accounting for limited IFN production in RSV-infected epithelial cells. To clarify the M antagonistic mechanism, we focused on M-interacting receptor of activated C kinase 1 (RACK1), which is an adaptor protein and a negative regulator of IRF3/7. Knockdown of RACK1 with small-interfering RNA attenuated the M-suppressed IFN-β response leading to increased IFN-β production and reduced RSV genome replication, confirming RACK1 as a critical host factor for efficient RSV infection. Our finding unravels an immune-intervening effect of RSV M protein on IFN response and further identifies RACK1 as a promising target for antiviral therapy. IMPORTANCE Respiratory syncytial virus (RSV) matrix (M) protein is indispensable for virion assembly and release. It is localized to the nucleus during early infection to perturb host transcription. However, the function of RSV M protein in other cellular activities remains poorly understood. In this study, several interferon response-associated host factors, including RACK1, were identified by proteomic analysis as RSV M interactors. Knockdown of RACK1 attenuates RSV-restricted IFN signaling leading to enhanced host defense against RSV infection, unraveling a role of M protein in antagonizing IFN response via association with RACK1. Our study uncovers a previously unrecognized mechanism of immune evasion by RSV M protein and identifies RACK1 as a novel host factor recruited by RSV, highlighting RACK1 as a potential new target for RSV therapeutics development.

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Dataset Information

Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response.

Publications

Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response.

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