• Rituparna Das, Mi-Sun Koo, Bae Hoon Kim, Shevin T Jacob, Selvakumar Subbian, Jie Yao, Lin Leng, Rebecca Levy, Charles Murchison, William J Burman, Christopher C Moore, W Michael Scheld, John R David, Gilla Kaplan, John D MacMicking, and Richard Bucala.
• Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA. dasrit@mail.med.upenn.edu
• Proc. Natl. Acad. Sci. U.S.A. 2013 Aug 6; 110 (32): E2997-3006.

AbstractMacrophage migration inhibitory factor (MIF), an innate cytokine encoded in a functionally polymorphic genetic locus, contributes to detrimental inflammation but may be crucial for controlling infection. We explored the role of variant MIF alleles in tuberculosis. In a Ugandan cohort, genetic low expressers of MIF were 2.4-times more frequently identified among patients with Mycobacterium tuberculosis (TB) bacteremia than those without. We also found mycobacteria-stimulated transcription of MIF and serum MIF levels to be correlated with MIF genotype in human macrophages and in a separate cohort of US TB patients, respectively. To determine mechanisms for MIF's protective role, we studied both aerosolized and i.v. models of mycobacterial infection and observed MIF-deficient mice to succumb more quickly with higher organism burden, increased lung pathology, and decreased innate cytokine production (TNF-α, IL-12, IL-10). MIF-deficient animals showed increased pulmonary neutrophil accumulation but preserved adaptive immune response. MIF-deficient macrophages demonstrated decreased cytokine and reactive oxygen production and impaired mycobacterial killing. Transcriptional investigation of MIF-deficient macrophages revealed reduced expression of the pattern recognition receptor dectin-1; restoration of dectin-1 expression recovered innate cytokine production and mycobacterial killing. Our data place MIF in a crucial upstream position in the innate immune response to mycobacteria and suggest that commonly occurring low expression MIF alleles confer an increased risk of TB disease in some populations.

51 keywords...

hide…