Influenza, a contagious respiratory illness caused by influenza virus, is responsible for substantial illness worldwide. Treatment options are few and the threat of a pandemic is constant. We have identified SERPINB1, an endogenous biological response modifier protein, also called MNEI (monocyte neutrophil elastase inhibitor) that protects the lung against bacterial infection and that, we hypothesize, may prove useful in protecting against influenza. Using rodent models of pulmonary infection, we showed that SERPINB1/MNEI protects innate anti-bacterial host defense and prevents inflammation and lung injury. SERPINB1/MNEI had no anti-bacterial effect in vitro, as anticipated, since its biochemical function is to selectively and efficiently inhibit neutrophil serine proteases (NSPs). The NSPs (elastase, cathepsin G and proteinase-3) are active proteases stored in neutrophil granules, which are released in large amounts in inflammatory lung disease and are powerful pathological agents that induce overproduction of inflammatory chemokines, direct proteolytic injury to lung tissue and loss of anti-microbial defense by degrading innate protective molecules. Prominent among the host defense molecules targeted by NSPs and protected by MNEI is pulmonary surfactant protein-D (SP-D), which neutralizes many influenza virus strains and enhances their clearance and protects host defense by anti- inflammatory action on alveolar macrophages. The proposed R21 (pilot) project will test the hypothesis that neutrophil serine proteases (NSPs) contribute to, and MNEI/SERPINB1 protects against, pathogenicity of influenza. We will use a mouse model of increased NSP activity recently generated in our laboratory by deletion of the SERPINB1/MNEI gene and will determine whether these mice show increased morbidity (loss of body weight) and mortality on infection with strains of influenza A virus (IAV). We will test for abnormalities of the innate immune response (early host response) of IAV infected mnei-/- mice by measuring viral titer, lung injury, inflammatory cytokines, influx of alveolar macrophages and neutrophils, necrosis of neutrophils, and levels of intact SP-D and NSP-cleaved inactivated SP-D. Finally, we will test whether recombinant MNEI rescues the defective response of mnei-/- mice and enhances the anti-viral host response of wild-type mice to influenza virus. Successful identification of NSPs as mediators of pathogenicity in influenza would be a step toward a novel therapeutic. As a therapeutic for influenza, inhibitors of NSPs and especially MNEI, a naturally occurring biological response modifier, would be mechanistically independent of current drugs and therefore suitable for combination use. Because MNEI functions by protecting innate host immunity, efficacy is anticipated for individuals with deficient adaptive immunity including the very young and very old. Importantly, MNEI has no need for binding viral determinants, and thus development of resistance is not anticipated. Influenza, a contagious respiratory illness caused by influenza virus, is responsible for substantial illness, and there is real threat of worldwide spread of emerging more virulent strains. We have identified MNEI (monocyte/neutrophil elastase inhibitor), an endogenous biological response modifier protein, that protects the lung against bacterial infection. In the proposed R21 (Exploratory/- Developmental Grant) project, we will use a mouse model developed in our laboratory to test the hypothesis that MNEI will prove useful in protecting against influenza. ? ? ?
| Hou, Lifei; Cooley, Jessica; Swanson, Richard et al. (2015) The protease cathepsin L regulates Th17 cell differentiation. J Autoimmun 65:56-63 |
| Farley, Kalamo; Stolley, J Michael; Zhao, Picheng et al. (2012) A serpinB1 regulatory mechanism is essential for restricting neutrophil extracellular trap generation. J Immunol 189:4574-81 |
| Gong, Dapeng; Farley, Kalamo; White, Mitchell et al. (2011) Critical role of serpinB1 in regulating inflammatory responses in pulmonary influenza infection. J Infect Dis 204:592-600 |
