Leshawndra Nyrae Price
$53,974
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Pennsylvania
National Institute of Allergy and Infectious Diseases (NIAID)
Tuberculosis (TB), a respiratory disease caused by the bacterium Mycobacterium tuberculosis (Mtb), is one of the leading causes of death by a single infectious agent, second only to SARS-CoV-2. In 2020, Mtb infected 10 million and killed 1.5 million people worldwide. 5-10% of those infected with Mtb will go on to develop active disease, and the most important risk factor is co-infection with human immunodeficiency virus (HIV). The resurgence of TB is tied to the emergence of the HIV epidemic, and one-third of HIV-associated deaths are due to TB. Development of most opportunistic infections after HIV infection is correlated with the degree of HIV- driven depletion of CD4+ T cells in the blood. Antiretroviral therapy, which prevents ongoing viral replication and CD4+ T cell depletion, has been revolutionary in managing HIV but is not curative. Importantly, people living with HIV remain more likely than those HIV-naïve to develop TB despite effective ART and normalized CD4+ T cell count. Immune dysregulation during HIV/Mtb co-infection is clearly more complex than simply CD4+ T cell depletion but remains incompletely understood. The hallmark of Mtb infection is the formation of granulomas: organized structures of immune cells that develop in response to Mtb-infected macrophages. Granulomas are critical for bacterial containment, and each is independent from others within a host. The function of a granuloma is closely tied to its spatial architecture, which determines cell-cell interactions necessary for function of immune cells. Outcomes of infection are likely dependent on the cumulative success or failure of individual granulomas in a host. I hypothesize that chronic SIV infection at the time of Mtb co-infection leads to aberrant macrophage and CD8+ T cell function within lung granulomas that favors microenvironments permissive to greater bacterial burden. Our laboratory’s established non-human primate (NHP) model of co-infection recapitulates human TB disease and uses simian immunodeficiency virus (SIV) as a surrogate for HIV. I propose to leverage this model to understand how SIV changes the immune microenvironment of granulomas during co-infection using multidisciplinary ex vivo and in vitro assays in combination with ex vivo imaging and systems immunology. In Aim 1, I will assess SIV infection of macrophages in granulomas and determine alterations in macrophage cell state. In Aim 2, I will determine how SIV drives altered CD8+ T cell function in granulomas. Results from the proposed aims will shed light on the complex immune dynamics important during SIV/Mtb co-infection, which will inform vaccine and therapeutics development.