R01AI162786

TB Meningitis: Evaluating CSF Immunology to Discover Hidden Disease and Potential Immunomodulatory Therapies - Abstract

In Sub-Saharan Africa, tuberculous meningitis (TBM) is the second most common cause of adult meningitis and a major cause of morbidity and mortality among people living with HIV. While host immunodeficiency clearly drives TBM pathogenesis, pathologic immune responses can also worsen the disease. The key drivers of HIV-associated TBM pathogenesis remain undefined but likely differ from HIV-negative TBM. Therefore, a study of the pathogenesis of TBM in HIV-infected humans is warranted and innovative. Opportunities for host-directed therapy in this vulnerable population remain unexplored.

To optimize treatment of HIV/TBM and improve survival, it is critical to fully characterize host responses at the site of infection and identify immune signatures associated with good or poor outcomes. To address this challenge, we bring our skills in experimental immunology of tuberculosis, matched with an experienced research team with a proven track record of clinical and translational research regarding AIDS-related meningitis in Uganda.

Diagnosing TBM is notoriously difficult. The poor sensitivity (~50%) of standard methodologies detects only a subset of those with TBM, likely with the highest CSF bacillary burden. In these patients, hypo-functional or pathologic immune responses, representing opposite extremes of immune function, may contribute to poor host control of infection. The higher sensitivity of Xpert Ultra enables semi-quantitative diagnosis of those with a lower burden of CSF bacteria and identifies a group with better immune control of the infection. Our preliminary data suggest that diagnosis with trace or very low Xpert Ultra is associated with better survival.

In this project, we propose a new microbiologic/immunologic framework for understanding TBM, categorizing patients based on the differing Xpert Ultra PCR cycle-threshold, which serves as a surrogate for CSF bacterial burden. We seek to interrogate this framework by defining disease outcomes including survival and neurocognitive testing in these different framework groups, while correlating these findings with immunologic analyses of cellular immune responses in the CSF. Our central hypothesis is that CSF immune signatures correlate with key aspects of TBM disease pathogenesis, including sensitivity of diagnostics, disease outcomes, and treatment responses.

To test this, we will perform high-parameter spectral flow cytometry and multiplex cytokine profiling of samples from the CSF and autopsy specimens of patients with HIV/TBM. By comparing these comprehensive immunologic data in groups of patients with either high or low CSF bacterial burden, in those with good or poor outcomes, and in the context of a clinical trial of standard vs high-dose rifampin treatment, we aim to define the key contributions of host immunity to TBM pathogenesis. If our hypothesis is correct, the implications of this research are that immunomodulatory therapy will need to be customized to address the paucity or excess of immune responses.

Regents Of The University Of Minnesota

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Minneapolis, Minnesota 554551507 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 377% from $696,169 to $3,322,837.