A Leishmania-Encoded Cytokine Manipulates the Host Response to Promote Parasite Persistence

Species of the parasite genus Leishmania infect millions of individuals worldwide resulting in a variety of clinical outcomes ranging from disfiguring cutaneous disease to potentially fatal visceral disease. Leishmania effectively invade humans and other mammalian hosts and evade immune-mediated clearance through manipulation of the host immune response. To this end parasites are capable of directly modulating their phagocytic host cells and dysregulating a potentially protective CD4 T cell response. A secreted parasite protein that may play a role in these activities has been recently described. Leishmania major expresses two genes for orthologs of the inflammatory cytokine macrophage migration inhibitory factor (MIF). Leishmania major-encoded MIF (LmMIF) was previously demonstrated to replicate mammalian MIF in its ability to bind the host MIF receptor and thereby regulate host cell signaling pathways and block apoptosis. In this work the role of LmMIF was explored in the context of L. major infection in vitro and in vivo. Both LmMIF genes were selectively removed from the parasite genome using double-targeted gene replacement in order to generate the mif-/-mutant strain. This strain was more susceptible to destruction by activated macrophages and demonstrated an impaired ability to block apoptosis and promote immune activation of antigen presenting cells in vitro. Investigations in a mouse model of infection demonstrated reduced inflammation in animals infected with the mif-/- parasite and reduced generation of effector CD4 T cells. However, effector Tcells formed in the absence of Lm MIF were less prone to exhaustion and apoptosis than those from mice infected with wild type L. major. Consequently, mice infected with mif-/- L. major were better able to control infection at late time points and better able to mount an effective T cell response to a secondary infection. These findings reveal a role for LmMIF in promoting parasite persistence in the host macrophage while simultaneously blocking long-term immunity to infection.