title: 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 LmMIF 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.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Holowka
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Tiago M
authors.initials: TM
authors.lastname: Castilho
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and.
authors.forename: Alvaro Baeza
authors.initials: AB
authors.lastname: Garcia
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Department of Epidemiology of Microbial Diseases, Yale University School of Medicine, New Haven, Connecticut, USA richard.bucala@yale.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D003001:Cloning, Molecular; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D018320:Leishmania major / Q000378:metabolism*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000469:parasitology*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D030781:Organisms, Genetically Modified; D040081:Protein Array Analysis; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D015800:Protozoan Proteins; C045084:invariant chain
keywords: CD4 T cells; MIF; apoptosis; exhaustion; inflammation