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

PLoS Pathogens

Erwan Pernet¹  James G. Martin¹  Donald C. Vinh¹  Jeffrey Downey¹  François Coulombe¹  Benoit Allard¹  Maziar Divangahi¹  Isabelle Meunier¹  Joanna Jaworska¹  Salman Qureshi¹  Philippe Joubert² 

[1] Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada;Department of Pathology, Quebec Heart and Lung Institute, Quebec, Quebec, Canada

关键词: Influenza A virus;    Infectious disease immunology;    Mitochondria;    Viral load;    Messenger RNA;    Interferons;    Apoptosis;    Macrophages;   

DOI  :  10.1371/journal.ppat.1006326

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY