Characterization of MTOR signaling pathway variants in previously healthy patients with non-HIV cryptococcosis

Authors

• JC Hargarten
• MJ Vaughan
• OCR Dean
• S Paul
• J Lacks
• PR Williamson

Abstract

Globally, Cryptococcus is an opportunistic fungal pathogen which causes major morbidity and mortality in a range of patient populations from the immunosuppressed to the previously healthy (PH) without obvious immune dysfunction. Cryptococcal infections in the PH are characterized by worse prognosis with mortality rate upwards of 30-50% despite antifungal therapy. Little is known about the molecular mechanisms driving the immune defects that lead to cryptococcosis in the PH. Our long-term goal is to identify and validate the major genetic and immunological defects leading to cryptococcosis susceptibility in the PH to inform human pathobiology and personalized patient care. Whole exome sequencing analysis on the largest cohort of PH patients identified rare alleles predicted to have deleterious functional consequences (CADD >30). Pathway analysis identified an enrichment in MTOR signaling (p-value =2.12E-06) defects. mTOR pathway activation is known to be critical for optimal T cell responses to fungal infections. In the present study, cryptococcosis patient MTOR variants were associated with loss of function defects in T cells. Ongoing genetic correction studies aim to functionally validate MTOR variants using patient cells. We next characterized the immunologic consequence of MTOR deficiency on susceptibility to Cryptococcus using established murine models of cryptococcosis. Mice deficient in appropriate mTOR signaling display increased susceptibility with dysregulation of effector T cell responses at the site of infection. These data suggest that appropriate MTOR signaling (particularly in CD4 T cells) is necessary for protection against infection. Ongoing experiments will further determine the mechanism by which MTOR signaling is required during cryptococcosis.

Scientific Focus Area: Clinical Research

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