Regulatory role of IFN-gamma on alveolar macrophage function during influenza infection (43.9)

Abstract

Abstract Secondary bacterial infection often follows pulmonary virus infection. We previously reported that pulmonary IFN-γ produced during influenza infection in mice inhibits initial bacterial clearance by alveolar macrophages. As a result, there was a 100-fold increase in bacterial burden in viral-infected WT mice 48 hr after pneumococcal challenge compared to IFN-γ-/- mice. Although IFN-γ production by CD4 or CD8 T cells alone was sufficient to inhibit bacterial clearance, TCR transgenic OT-I and OT-II mice had no detectable IFN-γ following influenza infection. Thus, virus-specific T cells are responsible for significant IFN-γ production. We found that the inhibitory effect of IFN-γ was correlated with down regulation of the class A scavenger receptor MARCO. Indeed, prior influenza infection had no effect on initial bacterial clearance in MARCO-/- mice. Inhibition of MARCO expression following influenza infection could be prevented by IFN-γ neutralization. Preliminary data suggest that IFN-γ inhibits MARCO expression by signaling through STAT1 and there is significant induction of SOCS1 and SOCS3 in alveolar macrophages during influenza infection. Ongoing work is designed to determine whether influenza-induced IFN-γ facilitates activation of a SOCS negative-feedback loop in alveolar macrophages, thereby suppressing innate protection against extracellular bacteria. (NIH grant #AI41715)