Inflammasome recognition of influenza virus is essential for adaptive immune responses

TLDR

Influenza virus is sensed by TLR7 and RIG‑I, triggering type I interferons and resistance, and TLR signaling is essential for CD4 T‑cell and IgG2a responses but not cytotoxic T lymphocytes. The study aimed to determine whether NOD‑like receptors contribute to viral recognition and adaptive immunity against influenza. The authors found that influenza infection activates lung NLR inflammasomes; while NLRP3 is required for inflammasome activation in some cells, protective CD4/CD8 T‑cell responses, mucosal IgA, systemic IgG, and immunity depend on ASC and caspase‑1 (not NLRP3), with caspase‑1 activation in hematopoietic cells being essential, establishing ASC inflammasomes as central to adaptive immunity to influenza.

Abstract

Influenza virus infection is recognized by the innate immune system through Toll like receptor (TLR) 7 and retinoic acid inducible gene I. These two recognition pathways lead to the activation of type I interferons and resistance to infection. In addition, TLR signals are required for the CD4 T cell and IgG2a, but not cytotoxic T lymphocyte, responses to influenza virus infection. In contrast, the role of NOD-like receptors (NLRs) in viral recognition and induction of adaptive immunity to influenza virus is unknown. We demonstrate that respiratory infection with influenza virus results in the activation of NLR inflammasomes in the lung. Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3. Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge. Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity. These results demonstrate that in addition to the TLR pathways, ASC inflammasomes play a central role in adaptive immunity to influenza virus.