The Role of Iron Homeostasis in Tuberculosis and the Innate Immune Response

The prevalence of tuberculosis cannot be understated, as nearly one in three people in the world are infected.  Disease progression and morbidity are heavily influenced by host iron status as the acquisition of iron by Myobacterium tuberculosis markedly increases myobacterial growth. Our study aims to 1) understand the regulation of iron homeostasis by the innate immune response and host genetics as well as 2) explore the potential of utilizing bacterial iron uptake as a novel treatment modality for tuberculosis.  Genetic studies have identified a strong association between mutations in the SLC11A1 gene, encoding a major iron transport protein, with susceptibility to infection and development of tuberculosis.  In addition, iron is an essential nutrient for Mycobacterium tuberculosis, the etiological agent of tuberculosis, which is actively acquired by the intracellular bacterium during infection of macrophages.  SLC11A1 is known to efflux iron from macrophage phagosomes harboring mycobacteria; however the regulation of SLC11A1 protein by the innate immune response is poorly understood.  Here, we demonstrate that disease associated SLC11A1 polymorphisms located in the 3’ untranslated region (UTR) of the mRNA results in differential binding of microRNA species present in the lung microenvironment.  Furthermore, activation of key innate immune responses against M. tuberculosis infection, the Toll-like receptor 2/1 and vitamin D pathways results in upregulation of SLC11A1 mRNA expression in human monocytes.  Therefore, the host SLC11A1 genotype may alter the innate immune regulation and function of this critical iron homeostasis pathway.