Serpin B1 prevents severe pulmonary influenza through specific effects on T cells and NK cells 2334958

Abstract Introduction The murine serpin b1a gene protects against H3N2 influenza A viral induced pathogenicity but the natural protein is intracellular and can be inactivated by ROS. We created a recombinant oxidation resistant murine form of the protein (serpin b1a OxR) and tested its function as a host-directed immunotherapy to prevent influenza induced weight loss and mortality in mice. Methods Three animal studies were performed. 1. A dose response study in H3N2 challenged mice to determine the optimal therapeutic dose of serpin b1a OxR. 2. An MO study to evaluate serpin b1a OxR induced changes in Innate and acquired immune cell responses, cytokines and select plasma analytes and biomarkers associated with H3N2 infection. 3. A study to determine if serpin b1a OxR prevents weight loss and death induced by other influenza type A and B strains (H1N1, B/Brisbane/60/2008 and B/Wisconsin/01/2010). Protein was administered i.p. prior to infection and on a q3d basis thereafter. Results Serpin b1a OxR reduced weight loss significantly and improved recovery and survival in female mice infected with H3N2 and B/Brisbane/60/2008. The protein modulated inflammation early through specific effects on immune cell populations, and suppression of elevated cytokines and markers of inflammation in the lungs and blood of treated animals. Of note, it significantly reduced NK cell count increases in the BALF of treated vs untreated H3N2 infected mice but increased them in the blood. Conclusion Serpin b1a OxR reduces morbidity and mortality induced by some Influenza A and B strains, notably H3N2 and B/Brisbane/60/2008. It also suppressed inflammation as evidenced by reduced proinflammatory cytokines, enzymes and markers of NET formation. Treatment specifically reduces increases in BALF NK cell counts. NK cells contribute to diffuse alveolar injury, impaired gas exchange, and increased susceptibility to secondary bacterial infections in severe influenza. Funding Source CDC, Redd Pharmaceuticals Inc Topic Categories Viral Immunology (VIR)