IFNAR-DEFECIENT NEUTROPHILS CONTRIBUTE TO THE CONTROL OF LEISHMANIA INFECTION

Lijun Xin, Ph.D.¹, D.A. Vargas-Inchaustegui,¹, S.S. Raimer, M.D.², B.C. Kelly, M.D.², J. Hu², L. Zhu², J. Sun, Ph.D., M.D.¹, and L. Soong, Ph.D., M.D.^1,3

¹Departments of Microbiology and Immunology, ²Dermatology, ³Pathology, Sealy Center for Vaccine Development, Institute for Human Infections and Immunity, UTMB

Background: 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. Objective: To define the role of endogenous type I IFN in the host innate response to cutaneous Leishmaniasis induced by L. amazonensis. Methods: Parasite infection in both footpad and ear models were used for evaluation of immune response and disease outcome, in which realtime PCR, flow cytometry, and adoptive transfer of bone marrow neutrophils were performed to confirm the role of IFNAR-/- neutrophils. Results: We found that following infection with L. amazonensis parasites, IFNAR-/- mice developed significantly attenuated disease with low levels of T-cell cytokines and antigen-specific IgG. Sustained neutrophils and lack of inflammatory monocytes recruitment contributed to the marked reduction in tissue parasite loads and inflammatory responses at early stage of infection in IFNAR-/- mice. In vitro studies showed that IFNAR-/- neutrophils enhanced macrophage-mediated parasite killing through more NE and MPO release and higher apoptotic tendency. While injection of IFNAR-/- neutrophils with parasite into WT mice reduced parasite survival, injection of WT neutrophils with parasite or adoptive transfer of WT bone marrow neutrophils into IFNAR-/- mice did enhance tissue parasite loads. Conclusions: Our results suggest an important role of IFNAR-/- neutrophils in the control of Leishmania infection and provide new information on innate immunity to protozoan parasites. Supported by Dr. Lynn Soong’s NIH grant.