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

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.

Dissecting host cell death programs in the pathogenesis of influenza

“…At low multiplicities of infection (MOI), necrosis is not substantially induced in M4 [116,26,129]. In addition, we and others have recently shown that IAV does not induce RIPK3mediated necroptosis in M4, both in vivo and in vitro, but, rather, RIPK3 plays a crucial role in the production of IL-1b [129] and IFN-I [130] and, as a result, mice deficient in RIPK3 are extremely susceptible to IAV infection. However, following severe infection with a high viral titer, IAV induces necroptosis through the RIPK1eRIPK3eCaspase 8 complex in vitro [86], suggesting a potential role for RIPK3-mediated necroptosis in depletion of M4 during infection with highly virulent strains.…”

Apoptosis and Necroptosis as Host Defense Strategies to Prevent Viral Infection

“…Furthermore, these studies noted reduced inflammatory responses to VV infection in the absence of these signaling components, suggesting an important role for necroptosis in the antiviral response to VV infection. However, TNFR and RIPK3 have additional necroptosis-independent activities [60][61][62][63], and the contribution of these activities to VV antiviral immunity in vivo have not been ruled out. Future studies investigating the susceptibility of mlkl -/and tnf1 -/-/mlkl -/mice to VV infection will clarify the role of TNFR-mediated necroptosis in antiviral immunity.…”

“…In vivo studies examining the role of cell death components in antiviral immunity have recently become more difficult to interpret with the identification of cell death-independent activities of RIPK1 and RIPK3. In contrast to IAV-infected MEFs, IAV-infected murine bone marrow-derived macrophages (BMDM) do not die but rather promote ifnβ transcription and translation in a RIPK1 or RIPK3-dependent manner, respectively [63]. In BMDM, RIPK3 negatively regulates an interaction between RIPK1 and MAVS resulting in decreased ifnβ transcription, while simultaneously promoting PKR phosphorylation and ifnβ mRNA stability.…”

“…In BMDM, RIPK3 negatively regulates an interaction between RIPK1 and MAVS resulting in decreased ifnβ transcription, while simultaneously promoting PKR phosphorylation and ifnβ mRNA stability. Consequently, ripk3-/-BMDM secrete less IFNβ, which may contribute to the increased susceptibility of ripk3-/mice to IAV infection [63]. RIPK3 has also been shown to promote cell death-independent neuroinflammation following subcutaneous West Nile virus (WNV) infection [62].…”

Necroptotic cell binding of β2‐glycoprotein I provides a potential autoantigenic stimulus in systemic lupus erythematosus

“…Impaired cytokine production in RIPK3 −/− mice has also been shown in viral models. Downey et al . found that the susceptibility of RIPK3 −/− mice to Influenza A virus was linked to an inability of RIPK3‐deficient macrophages to produce Type I IFN in the lungs of infected mice.…”