TARGETING THE GRANULOMA MICROENVIRONMENT TO IMPROVE TUBERCULOSIS TREATMENT

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 DESCRIPTION (provided by applicant): Targeting the Granuloma Microenvironment to Improve Tuberculosis Treatment Tuberculosis (TB) is a global scourge that is responsible for nearly 2 million deaths annually. A hallmark of TB infection is pulmonary granulomas - non-resolving, dense cellular masses that result from the immune response to the TB bacillus, Mycobacterium tuberculosis. We have found that TB granulomas share many physiological abnormalities with solid malignant tumors, including regions of hypoxia and necrosis, and abnormally dense extracellular matrix (i.e., extensive fibrosis). We have also discovered that granuloma- associated blood vessels are abnormal in structure and function (PNAS 2015). In tumors, we have found that the solid tissue components, cells and matrix, exert "solid stress" - a type of physical force - that can compress blood vessels (Nature 2004; PNAS 2012). Just as we have seen in tumors, fibrotic TB granulomas have high proportions of collapsed blood vessels, which we hypothesize is due to "solid stress". Vessel collapse can reduce granuloma blood perfusion, causing inefficient delivery of oxygen and drugs to the affected tissue. The resulting hypoxic and acidic conditions cause an immunosuppressive environment, thus polarizing the immune cells to a phenotype that is unable to effectively stave off the TB infection. Due to the inability of currently available treatment regimens to eradicate this devastating disease, it is clear that new treatment strategies are urgently needed. Building on our exciting preliminary findings, we now propose to exploit the striking similarities between TB granulomas and cancerous tumors to guide novel therapeutic approaches that target the granuloma microenvironment. We plan to investigate whether alleviating solid stress in granulomas via anti-fibrotic therapies, as we have done successfully in tumors (PNAS 2011; Nature Communications 2013), will improve vascular perfusion and enhance oxygenation and drug delivery, resulting in improvedimmune response and treatment outcome. In Aim 1, we will establish the relationship between granuloma matrix levels, "solid stress", and vessel collapse, and will investigate whether treating with an anti-fibrotic agent will remodel the matrix. In Aim 2 we will investigate whether treating with an anti-fibrotic agentsalleviates the adverse effects of solid stress in granulomas. Finally, in Aim 3, we will determine whether adjunctive anti- fibrotic therapy enhances the therapeutic efficacy of TB chemotherapy. To realize these aims, experiments will be carried out in a rabbit model of TB by our Collaborator, Dr. Clifton Barry at the National Institute of Allergy and Infectious Diseases, a leader in the field of TB. Furthermore innovative and robust imaging techniques will be applied to provide unprecedented molecular, cellular, structural, and functional knowledge of barriers to treatment in granulomas. Thus, for my predoctoral studies, I plan to apply my skills as an engineer to determine the role of "solid stress" in TB progression and to explore strategies to overcome barriers to TB treatment, while developing my skills in and knowledge of TB, cancer biology, and translational research.