Nucleotide-binding domain and leucine-rich-repeat-containing receptors (NLRs) are a family of cytosolic pattern recognition receptors with a range of functions including: pathogen/damage sensing, modulation of inflammatory signaling, and transcriptional control of genes controlling antigen presentation and processing. In response to PAMPs and DAMPs, some NLRs form multi-protein complexes known as inflammasomes, consisting of an NLR, the adaptor protein ASC, and caspase-1. Activation of inflammasomes results in caspase-1-mediated processing of pro-IL-1β and pro-IL-18 into their mature forms, which can be secreted. Inflammasome activation can also drive a pro-inflammatory form of cell death called pyroptosis.

NLRs have been implicated in the response to a number of viruses including influenza A virus (IAV). Influenza A virus represents an ongoing public health concern, infecting between 5-20% of the US population annually. The number and severity of infections can rise dramatically in years when strains emerge to which there is little pre-existing immunity within the population. Both innate and adaptive immune responses contribute to pathogen clearance and tissue damage during IAV infection, thus understanding the factors that initiate and influence these responses, including signaling downstream of viral sensing by pattern recognition receptors, is important. The NLRP3 inflammasome and other members of the NLR family shape both innate and adaptive responses to IAV. Activation of the NLRP3 inflammasome during IAV infection can be triggered by at least three stimuli: single-stranded viral RNA, H+ flux through the IAV-encoded M2 ion channel, and aggregates of the IAV virulence factor PB1-F2. Mice lacking either NLRP3 or caspase-1 exhibit higher mortality and compromised inflammatory cytokine production and cellular recruitment to the lungs.

To determine whether other NLRs are involved in the immune response to IAV infection, we infected multiple NLR-deficient mouse strains with IAV and tracked morbidity and mortality. Our findings from this initial screen indicate NLRC4 and NLRP12 have previously unappreciated roles during IAV infection. Elucidating the mechanisms by which they afford protection and/or mediate disease is the focus of our ongoing studies.

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