U19AI162568

Determinants of TB Control, Relapse, and Reinfection

Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), continues to be a severe global health problem. TB is multifaceted, but a central clinical and microbiologic feature of the disease is the ability of MTB to resist complete elimination, both by the host immune system and by chemotherapeutic agents with potent growth inhibitory activity.

This persistence in the face of immunologic and antibiotic pressure underlies several important facets of TB disease. Firstly, it includes the existence of latent tuberculosis infection (LTBI) and, in the setting of immunologic failure of LTBI control, its role in the genesis of active TB. Secondly, it involves the prolonged course of TB antibiotic therapy, which requires 6 months of multidrug therapy to achieve reliable clinical cure. Instead of producing complete bacterial eradication in all treated subjects, cure following TB chemotherapy is now understood to be an antibiotic-induced paucibacillary state in which prevention of relapse depends in part on poorly understood host factors.

The host and bacterial determinants that mediate these two interrelated types of persistence are only partially understood, creating a knowledge gap that the TRI-I-TBRU aims to fill. We propose a set of 3 intersecting projects and 3 cores, all focused on different facets of the problem of paucibacillary TB, both post-treatment and LTBI. The projects will use samples and clinical data from TB cohorts at our clinical site at GHESKIO in Port-au-Prince, Haiti, to examine the immunologic, microbiomic, transcriptomic, pharmacokinetic, and genetic factors that influence or predict the transition points between paucibacillary states of TB disease and active transmissible infection.

These human studies will be compared and contrasted with a new mouse model of paucibacillary infection that will allow us to test mechanistic hypotheses about the host and bacterial determinants of paucibacillary disease. This work will be conducted by a team of highly collaborative investigators who have worked well together for several years.

Weill Medical College Of Cornell University

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]

New York, New York 100654805 United States

Single Zip Code

Tuberculosis Research Units (U19 Clinical Trial Optional) (RFA-AI-20-020)

Amendment Since initial award the total obligations have increased 373% from $2,755,450 to $13,020,010.