Leishmania ‐encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence

ABSTRACT Leishmania major encodes 2 orthologs of the cytokine macrophage migration inhibitory factor (MIF), whose functions in parasite growth or in the host‐parasite interaction are unknown. To determine the importance of Leishmania ‐encoded MIF, both Lm MIF genes were removed to produce an mif –/– strain of L. major. This mutant strain replicated normally in vitro but had a 2‐fold increased susceptibility to clearance by macrophages. Mice infected with mif –/– L. major , when compared to the wild‐type strain, also showed a 3‐fold reduction in parasite burden. Microarray and functional analyses revealed a reduced ability of mif –/– L. major to activate antigen‐presenting cells, resulting in a 2‐fold reduction in T‐cell priming. In addition, there was a reduction in inflammation and effector CD4 T‐cell formation in mif –/– L. major ‐infected mice when compared to mice infected with wild‐type L. major. Notably, effector CD4 T cells that developed during infection with mif –/– L. major demonstrated statistically significant differences in markers of functional exhaustion, including increased expression of IFN‐γ and IL‐7R, reduced expression of programmed death‐1, and decreased apoptosis. These data support a role for LmMIF in promoting parasite persistence by manipulating the host response to increase the exhaustion and depletion of protective CD4 T cells.—Holowka, T., Castilho, T. M., Baeza Garcia, A., Sun, T., McMahon‐Pratt, D., Bucala, R. Leishmania ‐encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence. FASEB J. 30, 2249–2265 (2016). www.fasebj.org