Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis.

25 Feb 2020
Kumar R, Bunn PT, Singh SS, Ng SS, Montes de Oca M, De Labastida Rivera F, Chauhan SB, Singh N, Faleiro RJ, Edwards CL, Frame TCM, Sheel M, Austin RJ, Lane SW, Bald T, Smyth MJ, Hill GR, Best SE, Haque A, Corvino D, Waddell N, Koufariotis L, Mukhopadhay P, Rai M, Chakravarty J, Singh OP, Sacks D, Nylen S, Uzonna J, Sundar S, Engwerda CR

 

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4 T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4 T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4 T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.