Tuberculosis remains an important cause of infectious disease morbidity and mortality worldwide, and is a problem of particular concern to those in the armed forces. The organism that causes tuberculosis, Mycobacterium tuberculosis (Mtb), is an intracellular pathogen. Improved definition of those mechanisms by which the immune system recognizes intracellular infection provides direct application to improved vaccines and diagnostics. In this proposal, we will define the mechanisms by which human lung epithelial cells take up Mtb and the pathways by which Mtb antigens are processed and presented in the context of the MHC Class I molecule, MR1, to lung resident CD8+ T cells known as MAIT cells (mucosal-associated invariant T cells). Although the lung epithelium is the first line of defense against infection with Mtb, very little is known about the mechanisms of uptake and antigen presentation by epithelial cells to innate T cells. Improving our understanding of this interaction will be critical to rational design of better vaccines to serve the VA patient mission. To define the mechanisms by which human lung epithelial cells are taken up, we will perform a detailed analysis of the Mtb compartment in human epithelial cells in vitro, with regard to proteins known to be associated with uptake, vesicular trafficking, and antigen processing and presentation. To characterize the role that the epithelial cell Mtb compartment plays in MR1 antigen presentation, we will perform a detailed analysis of MR1 with regard to its cellular localization, association with the Mtb compartment, and antigen processing and presentation pathways. Our hypothesis is that Mtb is taken up by epithelial cells into compartments that are distinct from phagosomes of professional antigen presenting cells, and that trafficking of and presentation of antigen on MR1 are requisite steps in initiation and maintenance of Mtb-specific mucosal immunity.
Mycobacterium tuberculosis remains a leading cause of infectious mortality worldwide. TB incidence rates among members and Veterans of the Armed Forces returning from TB endemic regions such as Iraq and Afghanistan range up to 2%, a rate 1000 times greater than in the general population. Consequently, development of an improved vaccine for TB will serve the VA patient care mission. The development of an efficacious vaccine for tuberculosis will require a better understanding of the cellular immune response that is critical in the control of the disease. Although TB is predominantly a pulmonary disease surprisingly little is known about the initial events that occur in the human airway upon exposure to the pathogen. The long-term goal of this research is to understand the role of the epithelium in the early immune response to Mycobacterium tuberculosis in the human airway and lung.
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