Research Project
10247081
Project Summary There is a critical need for identification of factors contributing to TB-HIV co-infection outcomes and to prioritize new treatment modalities for treating drug-resistant TB in immune suppressed populations. Recently, it has been suggested that pharmacologic modulation of myeloid-derived suppressor cells (MDSC) may be an alternative to antimicrobial therapy for TB. MDSC are a transient immature myeloid cell population derived from a common progenitor cell, that have been shown to block T cell-activation by recruiting T-regulatory lymphocytes and inducing PD-1 expression on immune cells. In both cancer and chronic infectious diseases, MDSC have been associated with immune-suppression and dampening of the host?s immune response locally in tissue microenvironments, but the role of MDSC in Mycobacterium tuberculosis (Mtb) disease progression is unclear. In order to determine if MDSC are a useful target for adjunctive therapy for TB disease in immune suppressed populations, their role in TB disease needs to be elucidated. We hypothesize that MDSC contribute to local immune suppression in the lung during TB infection by influencing spatial infiltrates of immune cells and decreasing numbers and/or antimicrobial effectiveness of resident macrophage/monocyte populations within the granuloma. Myeloid derived suppressor cells (MDSC) have been associated with immune- suppression and dampening of the host?s immune response locally in tissue microenvironments, but the role of MDSC in Mycobacterium tuberculosis (Mtb) disease progression is unclear. We propose to determine if MDSC are a useful target for adjunctive therapy for TB disease by establishing numbers and localization patterns of MDSC in both human and mouse Mtb infected lung using a novel imaging platform, tissue cyclic immunofluorescence (t-CyCIF) to evaluate MDSC in the context of the granuloma. The long-term goal of our research is to establish the extent to which MDSC function and trafficking can be modulated pharmacologically to improve TB treatment outcomes. By determining the spatial co-localization of MDSC with other immune cells in human TB granulomas and establishing immune correlates of MDSC tissue localization with tuberculosis infection and control in Diversity Outbred (DO) mice we can evaluate MDSC as targets for host-directed therapy in TB treatment. In summary, we will use novel methodology, t- CyCIF, coupled with a mouse model of human genetic diversity, to generate new knowledge regarding the role of MDSC in TB disease. Methods to alter the expansion and infiltration of MDSC may aid TB vaccine design and immunotherapy to promote mycobacterial clearance in both HIV infected an uninfected patients.
