R01AI166305

Deep Spatial Immune Profiling of Granulomas and M. tuberculosis Adaptation to Disease and Treatment - Project Summary

Granulomas are hallmark pathological features of pulmonary tuberculosis (TB) and contribute to both containment of Mycobacterium tuberculosis (MTB) infection and progression to TB disease. However, we do not understand how the geospatial organization of immune cells and their communication networks impact the host immune functions that render a granuloma functionally permissive versus restrictive to MTB.

Stresses encountered by MTB during infection induce bacterial adaptations that promote MTB survival and drug tolerance, but we know little about the bacterial growth and metabolic changes induced within different granuloma microenvironments during disease or treatment and how the geospatial organization and immune state of the granuloma impacts bacterial physiology and killing.

To understand how cellular networks and granuloma spatial architecture determine the functional capacities of major granuloma types, we propose to develop a TB Granuloma Information System (TB-GIS) that will generate a geospatial map for individual granulomas and layer on additional data related to immunometabolic and antimicrobial functions, as well as MTB physiology and adaptation.

To characterize granuloma topology, we have exploited and optimized a novel high-plex imaging modality, T-CyCIF (Tissue Cyclic Immunofluorescence), which allows for deep geospatial immune profiling of tissue (30+ markers). We will leverage our well-established nonhuman primate (NHP) model of aero-genic MTB infection, which recapitulates the spectrum of human lung pathological lesions, and integrate additional cutting-edge tools and computational modeling to probe the host-pathogen interface in different TB granulomas (Aim 1).

We will also determine how perturbing granuloma topology with host- or pathogen-directed therapies impacts immune function and MTB metabolic state (Aim 2). Using the TB-GIS framework, we will quantify the relationship between specific granuloma features and cellular networks, immune function, and MTB physiology in treated and untreated animals.

We anticipate that these TB-GIS studies will transform our ability to predict granuloma function and help design new therapies to target granulomas harboring drug-tolerant bacteria that are difficult to clear with current treatment regimens.

Emory 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]

Atlanta, Georgia 303294208 United States

Single Zip Code

Understanding the Role of the M. Tuberculosis Granuloma in Tuberculosis (TB) Disease and Treatment Outcomes (R01 Clinical Trial Not Allowed) (RFA-AI-20-057)

Amendment Since initial award the total obligations have increased 285% from $1,255,581 to $4,831,256.