R01AI158963

Mathematical Modeling of Mycobacterium Tuberculosis Dissemination - Research Summary

Tuberculosis (TB), a disease caused by the bacteria Mycobacterium tuberculosis (MTB), remains a major infectious disease of humans worldwide. After the initial local infection of one site in the lung, MTB somehow disseminates in the lung and often spreads beyond the lung. In fact, extrapulmonary TB is a hallmark of the disease in young children and immunocompromised adults that is difficult to diagnose and treat. Our understanding of MTB dissemination, both within the lung and beyond, remains limited, however.

In this proposal, we assembled a team of scientists with expertise in computational biology (Ganusov, Aitchison, Duffy, Langston) and TB pathogenesis (Urdahl, Sherman, Behar) to provide quantitative understanding of mechanisms of MTB dissemination in the lung and systemically. To this end, we will be using a number of highly innovative techniques such as:

I) A novel animal model of TB: infection of mice with an ultra-low dose (ULD, 1-3 colony forming units, CFU) of MTB along with a set of 50 barcoded MTB strains,
II) An MTB strain H37RV-PBP10 with the replication clock plasmid, allowing us to estimate how quickly bacteria are eliminated in vivo, and
III) mRNA-based gene signatures predicting bacterial numbers in murine lungs and TB disease progression risk in humans.

With three complementary specific aims, we will provide detailed, quantitative understanding of fundamental processes of how MTB disseminates from the deposition in lung alveoli to the whole lung and systemically.

In Aim 1, we will determine the pathway of MTB dissemination within the lung using a novel model of ULD-infected mice that mimics better human infection than many other animal models. In particular, we will discriminate between alternative hypotheses of MTB spread in the lungs such as the "bubble model" (in which MTB spreads locally between lung lobes) and the "reseeding model" (in which MTB spreads hematogenously to different parts of the lung after disseminating systemically).

In Aim 2, we will determine the contribution of different cell populations, including MTB-specific CD4 T cell response, to kinetics of MTB dissemination systemically in mice infected with conventional doses (CD, 150 CFU) of MTB. To parameterize best-fit models, we will use data from experiments with MTB H37RV carrying the replication clock plasmid PBP10.

Finally, in Aim 3, we will attempt to improve on our recently derived mRNA-based gene signatures predicting CFU in murine lungs using cutting-edge graph theory-based methods of data dimensionality reduction. We will also perform experiments and define a new signature predicting disseminated TB in mice, and test its accuracy using data from monkeys and humans.

Taken together, by combining experimental data from highly innovative experiments involving novel techniques (ultra-low dose infections, barcoded strains, replication clock plasmid, microarray-based gene signatures), we will provide a quantitative understanding of how MTB disseminates in the lung and systemically in the body.

Texas Biomedical Research Institute

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]

San Antonio, Texas 782275302 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 434% from $591,637 to $3,160,630.