An ineffective host response limits the successful treatment of many infections. Our research has focused on the role in the host response of macrophage migration inhibitory factor (MIF), an innate cytokine that we initially cloned and found to upregulate pattern recognition receptors and inhibit activation-induced apoptosis. Depending on the infectious agent or on host context, MIF can protect from infection or promote damaging inflammation~ a duality confirmed by human genetic studies showing an association between high expression MIF alleles and protection from bacterial pneumonia but more severe malaria. Our recent studies indicate an important role for MIF in the clinical expression of tuberculosis (TB). In subjects co-infected with HI and TB, a population central to the global TB epidemic, low genetic MIF expressers were 2.4 times more frequently identified to have mycobacterial bacteremia. The converging epidemics of HIV and TB, which highlight the critical role of the host response, together with the increasing prevalence of drug-resistant mycobacteria provide imperatives for investigating strategies for improving diagnosis and therapy. With our accruing insight into the biology and structure-function of MIF, we propose in this renewal application to define the role of the MIF locus in TB and to evaluate a novel pharmacologic approach to augment MIF action. Our three Specific Aims are: 1. Determine the Relationship between MIF Polymorphisms and the Risk of Developing Tuberculosis in Susceptible Populations. We hypothesize that genotypic low MIF expressers with HIV are at increased risk for tuberculosis. We will define the relationship between MIF genotype and the risk of acquiring TB or progressing to TB disease in two studies of relevant clinical cohorts. In the first, we wll conduct a case-control study in 180 adults with confirmed HIV/TB to assess the relationship between MIF genotype and pulmonary disease. In the second, we will perform a longitudinal study of 858 HIV-infected patients followed for >4 years. The relationship between MIF genotype and the risk of acquiring TB or progressing to TB disease will be determined. 2. Define the Transcriptional Regulation of the MIF -794 CATT5-8 Promoter Microsatellite. Although several studies have established associations between variant MIF alleles and the susceptibility or severity of different infections, there is no information about the molecular biology of the MIF promoter microsatellite. We hypothesize that the -794 CATT5-8 sequence binds discrete nuclear proteins to organize a transcription complex. We will identify these proteins and establish their functionality in vitro. 3. Evaluate the Therapeutic Potential of Pharmacologic MIF Modulation. A collaborative program at Yale has led to the discovery of pharmacologically auspicious, small molecule MIF agonists that increase MIF signaling through its receptor. We will obtain proof-of-concept for the application of MIF agonists to augment host anti-mycobacterial responses in cell-based and murine mycobacterial infection models.
A genetic association between commonly occurring MIF alleles and TB has been identified and may explain the increased risk of certain populations to this disease. As TB is the leading cause of infectious disease death globally and there is an increasing prevalence of drug resistant mycobacteria, investigation of host mechanisms that may lead to improved diagnostic and therapeutic interventions is highly desirable. The planned study will broaden our understanding of MIF biology applicable to several infectious diseases and it will accelerate consideration of MIF agonists as a novel immunotherapeutic strategy;potentially in individuals who are genotypic low MIF producers, and may add a new tool to combat the global TB epidemic.