Abstract Globally, central nervous system (CNS) infections have one of the largest burdens of death and disability, particularly among persons with weaken immune systems due to the extremes of age, immunosuppressive medicines, or HIV. Cryptococcal meningitis causes 15-19% of AIDS-related deaths, and TB-meningitis is the deadliest form of tuberculosis (TB). These CNS infections are neglected diseases. This K24 Midcareer Investigator Award in Patient-Oriented Research proposal seeks to continue a successful clinical and translational research portfolio in humans with CNS infections to impact the international guidelines for what is the standard of medical care in low-, middle-, and high-income countries. The research portfolio includes leading and mentoring clinical cohorts and randomized clinical trials on: 1) FDA-field trials for meningitis diagnostics; 2) meningitis treatment; 3) optimizing supportive care for CNS infections; 4) preventing cryptococcosis; 5) exploring immunopathogenesis in humans relative to survival and 6) neurocognitive outcomes; as well as 7) using health economics to inform international and US policy. This proposal is submitted by a mid-career investigator focused on improving the diagnosis, treatment, and prevention of neuro-infections. In 16 years as a faculty, the candidate has mentored >60 students, trainees, and junior faculty. Current mentees include: 6 K-awardees, 1 Wellcome Trust PhD fellow, 1 MD/PhD student, 12 under-represented minorities, as well as MD and MPH students. The candidate serves as program director for a T32 training award for infectious diseases fellows. Since 2019, the K24 candidate has published 163 manuscripts (NIH iCite RCR mean = 3.47, ~85th percentile), reflective of effective leadership of a highly productive interdisciplinary meningitis research team conducting relevant research. The K24 seeks to continue a productive research platform for HIV-related neuro-infections, which are neglected diseases. There is a track record of creativity, innovation, and pursuit of clinically relevant research which impacts clinical care in the U.S. and abroad to improve the prevention, diagnosis, and survival of those persons living with HIV. Specific Aims are: 1) Enroll a prospective cohort of HIV+ persons with meningitis to enable diagnostic field trials and mentee substudies; 2) Develop new clinical trial protocols to investigate new agents for cryptococcal meningitis and TB meningitis; 3) Develop immunologic framework to characterize distinct subsets of AIDS- related neuro-infections in the setting of HIV therapy with a focus on future host directed therapy. Training objectives of this K24 include 1) further refinement of leadership skills to lead a multi-disciplinary team; 2) developing further mentoring skills through formal training and workshops; 3) developing proficiency in single-cell RNA-sequencing to better characterize CSF immune responses.