Mechanistic Target of Rapamycin (MTOR) in human and murine cryptococcosis

/ABSTRACT Cryptococcus (Cn) species have a global impact on human health as an environmental, opportunistic fungal pathogen that most commonly presents as pulmonary disease or meningoencephalitis (CM) causing an estimated 180,000 deaths annually in a range of patient populations. Despite knowing that T-cells are required for immune protection, little is known about the molecular mechanisms driving susceptibility to cryptococcosis. Our long-term goal is to identify genetic and immunological defects leading to susceptibility to Cn to inform pathobiology and personalized care. To address this goal, whole exome sequencing was performed on a cohort of previously healthy patients without known immunosuppression to identifying rare alleles associated with cryptococcosis and predicted to have deleterious functional consequences. For the first time, gene enrichment pathway analysis identified MTOR signaling deficits as enriched in this population. The goal of this proposal is to determine whether identified MTOR variants cause dysfunction in MTOR signaling associated with increased susceptibility to cryptococcal disease. Our central hypothesis is that MTOR deficiency predisposes patients to cryptococcosis and suggests functional MTOR signaling is required to clear Cn. This will be accomplished by: (Aim 1) Characterizing the immunologic consequence of MTOR deficiency on susceptibility to Cn using established murine models of cryptococcosis; and (Aim 2) Determining how patient MTOR variants alter cell signaling and function in patient lymphocytes. The results from this proposal will begin to elucidate for the first time mechanistically how human genetic variants in a single gene (MTOR) are associated with specific susceptibility to cryptococcosis in previously healthy individuals with no known immunologic defects. Thus, these results will provide novel insights into human disease susceptibility to Cn and reveal the protective immune responses affected by MTOR deficiency. Ultimately, expanding our definition for who is at risk for cryptococcosis and suggesting improved treatment opportunities for cryptococcosis patients identified to have aberrant MTOR signaling through pharmacologic modulation of cell-specific immunity. The applicants career goal is to become an independent scientist in the field of fungal immunology with a focus on understanding the mechanism by which specific host genetic defects lead to susceptibility of previously healthy patients to cryptococcosis. To meet this goal, the applicant will begin the process of transition to an independent scientist by beginning to apply for tenure-track faculty positions in fall 2024 cycle. Further, the applicant proposes a career development plan that will allow her to gain more experience in host genetic susceptibility/fungal immunology, grant writing, and leadership skills through practical experience, formal course work, and mentoring. Highly accomplished collaborators specialized in similar areas as the proposed research project will mentor the applicants career development and provide expertise on different aspects of the project. Project Number: 1K22AI179795-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Jessica Hargarten | Institution: RUTGERS BIOMEDICAL AND HEALTH SCIENCES, Newark, NJ | Award Amount: $160,640 | Activity Code: K22 | Study Section: Allergy, Immunology, and Transplantation Research Committee[AITC] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K22AI17979501A1