NLR control of antiviral defense in the respiratory mucosa

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DESCRIPTION (provided by applicant): Influenza A is a major human pathogen that causes severe illnesses in over 5 million people worldwide annually, and is classified as a NIAID Category C Priority Pathogen. Innate immunity plays an important role in both rapid clearance of virus as well as in generating long-term protective immunity. Influenza virus infection is known to be recognized by two innate sensors, the Toll like receptor 7 (TLR7) and cytosolic RNA sensor RIG-I. However, the role of NOD-like receptor (NLR) is recognition of influenza virus, and the consequence of activation of inflammasomes in immune responses to influenza is unknown. In the Preliminary Studies section, we provide clear evidence that inflammasomes are activated in vivo during respiratory influenza infection. More importantly, we demonstrate that inflammasome-induced IL-1beta provides a key signal to recruit variety of cell types to the lung mucosa, and to initiate CD4, CD8 T cell and antibody responses. Mice deficient in inflammasomes are rendered more susceptible to viral replication and death. In this application, we build on these observations to propose to elucidate the mechanisms by which inflammasomes mediate adaptive immune responses to respiratory infection with influenza virus through two specific Aims. In the first Aim, we propose to examine the importance of NLR stimulation in dendritic cells in their antigen presenting capacity to stimulate na¿ve CD4 and CD8 T cells to flu infection in the lung. In the second Aim, we will examine the B cell-intrinsic requirement for NLR inflammasomes in the generation of antibody responses to influenza. Specifically, we will examine the importance of B cell activation through inflammasomes in IgA and IgG responses in the upper and lower respiratory tracts, respectively. Basic understanding of how the innate sensors orchestrate the generation of protective immune outcomes will help establish important foundation with which to design immunological interventions and preventative measures against flu-associated diseases. RELEVANCE: Influenza virus is a major public health risk, and recent advances in genetic engineering have raised concerns about the use of influenza as a biological threat. The goal of this R21 proposal is to understand how innate recognition of influenza virus through the NOD-like receptors enables key immune cell-types, dendritic cells and B cells, to orchestrate adaptive immune responses and antiviral protection in the lung.