Format

Send to

Choose Destination
FASEB J. 2016 Jun;30(6):2249-65. doi: 10.1096/fj.201500189R. Epub 2016 Mar 8.

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

Author information

1
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and.
2
Department of Epidemiology of Microbial Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.
3
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.

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.

KEYWORDS:

CD4 T cells; MIF; apoptosis; exhaustion; inflammation

PMID:
26956417
PMCID:
PMC4871794
DOI:
10.1096/fj.201500189R
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center