1152. Macrophage Migration Inhibitory Factor (MIF) is a Critical Mediator of the Tuberculous Immune Response
Session: Poster Abstract Session: Innate and Adaptive Immunity to Infections
Saturday, October 22, 2011
Room: Poster Hall B1

Background: Macrophage migration inhibitory factor (MIF) is an innate cytokine encoded in a functionally polymorphic genetic locus.  MIF contributes to detrimental inflammation in some models, but may be crucial for controlling infection by intracellular pathogens.

Methods: We previously showed MIF-related defects in macrophage mycobacterial control as well as reduced survival and increased lung pathology in M. tb infected mif knock-out mice.  In this study, we examine the serum level of the cytokine as well as the distribution of MIF high and low expresser genotypes in two cohorts.  The first, from the Tuberculosis Clinical Trials Consortium (TBTC), consists of 143 patients with tuberculosis from study sites in the United States.  The second cohort contains 464 patients enrolled in a sepsis outcomes study from Uganda. 

 

Results: In the TBTC cohort, serum MIF levels were elevated in tuberculosis patients compared to healthy controls, (p<0.001).  Patients with high expresser MIF genotypes had higher circulating MIF than low expressers (p<0.05).  There also was a trend towards higher MIF levels in patients who had positive sputum cultures and >1+ organisms on microscopy (p=0.06, 0.07).  In the Ugandan sepsis cohort, M. tb was the most frequently identified causative organism (21%).  Sepsis patients with high expresser MIF genotypes were more likely to survive, OR 1.97 (CI 1.11-3.48).  Distribution of MIF genotypes was significantly different in patients who had positive M. tb blood cultures vs. those who did not (χ2=0.03).  Low expresser MIF genotypes were more frequently identified among patients with tuberculous bacteremia compared to those with negative cultures (OR 2.25, CI 1.29-3.93).

Conclusion: This study demonstrates that MIF is elevated and correlated with genotype in patients with tuberculosis.  Also, patients with a low expresser MIF genotype are enriched in a population with M. tb bacteremia, where mortality is also decreased in high expressers of the cytokine.  Our work indicates that MIF is crucial to mycobacterial control at the level of the macrophage, mouse, and infected patient population.  These findings have clinical implications for determining genetic risk for tuberculosis disease and for developing immunomodulatory therapies.

 


Subject Category: E. Innate and adaptive immunity to infections, including vaccine immunology

Rituparna Das, MD1, Shevin T. Jacob, MD, MPH2, Christopher Moore, MD3, William Burman, MD4, Rebecca Levy, BA5, Lin Leng, PhD5, W. Michael Scheld, MD, FIDSA6 and Richard Bucala, MD, PhD7, (1)Infectious Disease, Yale School of Medicine, New Haven, CT, (2)Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, (3)University of Virginia School of Medicine, Charlottesville, VA, (4)University of Colorado Health Sciences Center, Denver, CO, (5)Yale University School of Medicine, New Haven, CT, (6)University of Virginia Health Systems, Charlottesville, VA, (7)Rheumatology, Yale School of Medicine, New Haven, CT

Disclosures:

R. Das, None

S. T. Jacob, None

C. Moore, None

W. Burman, None

R. Levy, None

L. Leng, None

W. M. Scheld, None

R. Bucala, None

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.