title: Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis.
abstract: Macrophage 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.
authors.affiliation: Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA. dasrit@mail.med.upenn.edu
authors.forename: Rituparna
authors.initials: R
authors.lastname: Das
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Koo
authors.forename: Bae Hoon
authors.initials: BH
authors.lastname: Kim
authors.forename: Shevin T
authors.initials: ST
authors.lastname: Jacob
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Subbian
authors.forename: Jie
authors.initials: J
authors.lastname: Yao
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Rebecca
authors.initials: R
authors.lastname: Levy
authors.forename: Charles
authors.initials: C
authors.lastname: Murchison
authors.forename: William J
authors.initials: WJ
authors.lastname: Burman
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Moore
authors.forename: W Michael
authors.initials: WM
authors.lastname: Scheld
authors.forename: John R
authors.initials: JR
authors.lastname: David
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.forename: John D
authors.initials: JD
authors.lastname: MacMicking
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000276:immunology; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011110:Polymorphism, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D014454:Uganda; D055815:Young Adult; D000099181:Dectin-1
chemical_list: D016207:Cytokines; D037181:Lectins, C-Type; D008263:Macrophage Migration-Inhibitory Factors; D000099181:Dectin-1