The roles of type I IFN receptor and neutrophils in regulating innate immunity to Leishmania parasites (133.26)

Abstract

Abstract Type I IFNs exert diverse effector/regulatory functions in innate and adaptive immune responses to viruses and bacteria; however, their roles in parasitic infections are less clear. It has been reported that parasite-induced type I IFNs are critical for NO-dependent disease control, and that administration of IFN-β has a dose-dependent protective effect in L. major-infected mice. Surprisingly, we found that following infection with L. amazonensis parasites, IFNAR-/- mice developed significantly attenuated disease with low levels of cytokines and sera antigen-specific IgG. The marked reduction in tissue parasite loads and inflammatory responses even at 3 days of infection in IFNAR-/- mice suggests the possibility of neutrophil-mediated parasite clearance. First, although WT and IFNAR-/- mice were efficient in recruiting CD11b+F4/80+Gr1+ peritoneal neutrophils at 6 h post-injection of parasites, knockout mice displayed unique phenotypic changes in Gr1lowCD11bhigh macrophages and Gr1highCD11blow neutrophils at 24 h. Second, in addition to release more neutrophil elastase and myeloperoxidase, IFNAR-/- not STAT1-/- neutrophils had significantly higher rates of spontaneous and infection-induced apoptosis than did their WT controls. Third, while macrophages alone responded comparably to parasites, the interactions between macrophages and IFNAR-/- neutrophils (but not WT and STAT1-/- neutrophils), greatly enhanced parasite killing. Finally, adoptive transfer of WT bone marrow neutrophils into IFNAR-/- mice did enhance tissue parasite loads. This study suggests an important role for type I IFNs in regulating neutrophil turnover and Leishmania infection and provides new information on innate immunity to protozoan parasites.