Thursday, November 21, 2024
11/21/2024
Project Summary Cryptococcal meningitis (CM), caused by the opportunistic fungal pathogen Cryptococcus neoformans (Cn), is a leading cause of HIV-related mortality worldwide. In healthy individuals, exposure to Cn in early childhood results in a pulmonary latent infection that is asymptomatic, but leads to the formation of lung granulomas. Following HIV-associated compromise of the immune system, control of latent Cn infection within pulmonary granulomas is lost and the fungal pathogen disseminates to cause meningitis. The host immune cells and effector functions critical for establishing and maintaining control of latent Cn infections have not been identified. Clearance of latent infections is warranted in the context of advanced HIV care. Understanding how the healthy immune response controls latent Cn infection is needed to: 1) define critical immune functions that prevent disease, 2) determine why a healthy immune system is unable to eradicate latent infections, and 3) develop targeted therapies that mitigate disease progression in HIV patients with CM. Using a novel mouse inhalation model of latent cryptococcosis developed in our lab, I will test my central hypothesis that a Th1 CD4 T-cell response is necessary and sufficient to control the latent pulmonary Cn infection, but is unable to clear the infection due to intrinsic deficiencies in interferon-γ (IFNγ) signaling caused by persistent Cn survival within granulomas. In Aim 1, I will combine laser capture microdissection with RNA sequencing to determine the cellular and effector functions responsible for containing Cn within granulomas. In Aim 2, I will use a mouse model that mimics HIV-induced CD4 depletion and post-mortem granulomatous lung tissue biopsies from HIV patients with CM to investigate how HIV-induced loss of CD4 T-cells disrupts control of latent Cn infection within granulomas. In Aim 3, I will use adoptive T-cell transfers and exogenous IFNγ supplementation to elucidate the CD4 T-cell subset and effector functions responsible for controlling latent Cn infection. The long-term goal of these studies is the development of immune-regulated therapeutic strategies for HIV- associated CM. These strategies include clearing latent Cn infection prior to HIV-immunosuppression in at-risk individuals and mitigating disease progression in HIV/AIDS patients by replacing the essential Cn-specific CD4 T-cell subset required for control of Cn infections. This proposal will lay the necessary groundwork for developing therapies that specifically target Cn infection, but avoids eliciting immune reconstitution inflammatory syndrome in HIV/AIDS patients with CM. The proposed research and training plans provide a rigorous program for successful completion of MD- PhD degrees, and will further my development into a successful academic infectious disease physician scientist who drives cutting-edge translational research in HIV/AIDS and HIV-associated opportunistic pathogens.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
