R01AI175935

Mycobacterium avium complex pulmonary infection: Immunologic and transcriptomic signatures of disease and treatment response - Project summary/abstract

We seek to define immunologic and transcriptomic signatures of Mycobacterium avium complex (MAC) pulmonary disease and microbiologic treatment response.

Nontuberculous mycobacteria (NTM) are environmental pathogens that are present in the soil and water.

MAC is the most common cause of NTM pulmonary disease, causing chronic, debilitating disease in predominantly older patients with underlying lung disease.

Prior work has illustrated that incidence rates of MAC pulmonary disease are increasing substantially, particularly among women.

Currently, the role of the host response in the development of disease is not well described.

Treatment, when necessary, consists of 3-4 antibiotics for 18+ months.

There is an urgent need to fill the critical gaps in knowledge of factors associated with disease burden and treatment response.

Our lack of understanding poses significant diagnostic and therapeutic challenges.

First, it is often difficult to discern colonization vs. disease caused by these organisms, and second it is difficult to predict who will benefit from therapy, or who will remain disease-free after therapy completion.

There is a need for non-invasive biomarkers of disease burden and treatment response, to limit exposure to computed tomography scan radiation that is currently used to monitor disease along with acid-fast sputum culture and patient-reported symptoms.

Based on M. tuberculosis literature coupled with observations of NTM disease in the setting of anti-tumor necrosis factor therapy, the TH1 response could explain NTM pulmonary disease pathogenesis in some patients.

This prospective biobank enrolls patients in a sub-study of our ongoing MAC2V3 pragmatic clinical trial, as well as others who meet American Thoracic Society/Infectious Disease Society of America clinical, radiographic, and microbiologic disease criteria and are starting treatment for MAC pulmonary disease.

This builds on our existing NTM clinical trials network infrastructure and extensive experience developing and managing the Northwest NTM Biobank.

The biobank has supported collaborations between MPIs Drs. Winthrop and Lewinsohn to conduct preliminary feasibility studies of immune correlates of disease.

MPIs Drs. Lewinsohn and McWeeney have a longstanding history of collaboration.

During years 1-4, we will collect blood and sputum samples longitudinally from patients initiating treatment for MAC pulmonary disease and conduct aims 1A and 2A.

During years 3-5 we will complete aims 1 and 2.

In this setting we will conduct high throughput cytometry time-of-flight (CyTOF) analysis of peripheral blood mononuclear cells to identify an immune signature of disease and microbiologic treatment response.

Similarly, we will conduct whole blood next generation RNA sequencing to identify an RNA transcriptome signature of disease and microbiologic treatment response.

Ultimately, the development of a disease signature and biomarkers predictive of treatment response could help better guide therapeutic and diagnostic decision-making with regard to MAC pulmonary disease.

Oregon Health & Science 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]

Portland, Oregon 972393011 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 268% from $873,166 to $3,209,026.