Targeting of the surfactant protein A receptor SP-R210L variant by influenza A virus in macrophages. (INM8P.440)

Abstract

Abstract Alveolar macrophages (AM) are critical for controlling IAV infection by limiting virus release and by initiating innate and adaptive immunity. Surfactant proteins A (SP-A) and D (SP-D) are a primary line of defense against IAV. Previous studies demonstrated that the SP-A receptor SP-R210 mediates clearance of SP-A-opsonized pathogens. Macrophages express two variants, SP-R210L and SP-R210S, though SP-R210L is predominant on AMs. Here, we studied the role of SP-R210 in IAV infection. We show that disruption of SP-R210L in vitro blocked IAV infection with H3N2 and H1N1 IAV strains. Flow cytometry and microscopy experiments showed that SP-R210L is required for endocytic trafficking of IAV to the nucleus. Furthermore, SP-R210L-mediated infection of macrophages was coupled to the production of TNFα. Interestingly, SP-R210L-deficient macrophages were hyper-responsive to the TLR7 ligand imiquimod. Accordingly, IAV inhibited SP-R210L expression in a time-dependent manner. To address these results in vivo, we studied transgenic mice with conditional disruption of SP-R210 in macrophages; SP-R210-deficient mice were significantly more susceptible to IAV infection as indicated by increased morbidity, decreased survival, and severe lung histopathology compared to WT littermates. Taken together, these findings support the model that by co-opting SP-R210L in AMs, IAV causes a functional ‘knock-down’, reducing the beneficial function of SP-R210L and leading to excessive lung inflammation.