SP-R210 (Myo18A) enhances influenza A virus pathogenicity by alveolar macrophages and dendritic cells in vivo

Abstract

Abstract Alveolar macrophages (AMs) are critical for the host response to severe influenza A virus (IAV) infection; IAV is known to cause abortive infection in AMs that is thought to initiate the lung’s immune response to the virus. Our recent studies indicate that the surfactant protein A receptor SP-R210 mediates IAV entry in AMs. Based on these findings, we asked whether SP-R210 modulates the host response to IAV infection. To address this question, we used SP-R210 floxed mice to delete SP-R210 in CD11c-Cre (dendritic cells and AMs) or Clec9A-Cre (CD103+ dendritic cells) expressing cells. Mice were infected intranasally with a sublethal dose of 1,000 FFU IAV PR8 strain and morbidity was monitored daily by body weight. We found that disruption of SP-R210 significantly reduced susceptibility to infection in both CD11c-CRE/SPR210+/− and Clec9A-Cre/SP-R210+/− as indicated by accelerated body weight recovery 10 days after infection compared to control littermates. The increased recovery of SP-R210-deficient mice was accompanied by a faster decrease in viral titer 7 to 14 days post infection (dpi) as well as increased numbers of CD4+ and CD8+ T cells 14 dpi. Furthermore, flow cytometry analysis revealed significantly increased number of CD11b+Ly6C++Ly6G- and CD11b+SiglecF+ macrophages and AMs in SP-R210-deficient mice, respectively. Consistent with these results, real time qPCR showed persistent suppression of the AM marker SiglecF in control littermates whereas inhibition of SiglecF expression in SP-R210-deficient mice was transient returning to near normal levels by 14 dpi. Taken together, these findings support the model that IAV causes depletion of AMs through SP-R210 disrupting restoration of immune homeostasis after IAV infection.