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RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to Influenza A virus infection.

RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to Influenza A virus infection.
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Downey J, Pernet E, Coulombe F, Allard B, Meunier I, Jaworska J, Qureshi S, Vinh DC, Martin JG, Joubert P, Divangahi M,


Downey J, Pernet E, Coulombe F, Allard B, Meunier I, Jaworska J, Qureshi S, Vinh DC, Martin JG, Joubert P, Divangahi M, (click to view)

Downey J, Pernet E, Coulombe F, Allard B, Meunier I, Jaworska J, Qureshi S, Vinh DC, Martin JG, Joubert P, Divangahi M,

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PLoS pathogens 2017 04 1413(4) e1006326 doi 10.1371/journal.ppat.1006326

Abstract

The type I interferon pathway plays a critical role in both host defense and tolerance against viral infection and thus requires refined regulatory mechanisms. RIPK3-mediated necroptosis has been shown to be involved in anti-viral immunity. However, the exact role of RIPK3 in immunity to Influenza A Virus (IAV) is poorly understood. In line with others, we, herein, show that Ripk3-/- mice are highly susceptible to IAV infection, exhibiting elevated pulmonary viral load and heightened morbidity and mortality. Unexpectedly, this susceptibility was linked to an inability of RIKP3-deficient macrophages (Mφ) to produce type I IFN in the lungs of infected mice. In Mφ infected with IAV in vitro, we found that RIPK3 regulates type I IFN both transcriptionally, by interacting with MAVS and limiting RIPK1 interaction with MAVS, and post-transcriptionally, by activating protein kinase R (PKR)-a critical regulator of IFN-β mRNA stability. Collectively, our findings indicate a novel role for RIPK3 in regulating Mφ-mediated type I IFN anti-viral immunity, independent of its conventional role in necroptosis.

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