R01AI163160

Dysregulated Asthmatic Epithelial Interferon Responses to Viruses Drive Exacerbation, T2 Inflammation, and Airway Remodeling - Project Summary:

Asthma exacerbations among U.S children result in 640,000 emergency department visits, 280,000 hospitalizations, and 14 million missed school days annually. Type 2 (T2) cytokine-driven inflammation characterizes the most common asthma endotype in children (T2-HIGH) and is associated with viral-triggered exacerbation risk. Although treatment of T2-HIGH asthma with inhaled corticosteroids (ICS) or biologics reduces exacerbation frequency in many patients, these treatments are suboptimal with millions of viral-triggered exacerbations annually in the U.S. Furthermore, treatment of T2 inflammation does not alter the natural history of asthma, and effective treatments for the 30% of children and adults with T2-LOW asthma are lacking.

Viral infections trigger most exacerbations in asthmatic children, of which human rhinoviruses (HRV) are the most common. Some have reported deficient type I and III interferon (IFN) responses by asthmatic airway epithelial cells (AECs) and postulated that deficient IFN responses predispose to exacerbations. However, this concept is controversial as others have not observed deficient IFN responses to viruses by asthmatic AECs. We have observed that greater AEC IFN expression at baseline or in response to ex vivo viral infection is associated with lower lung function in asthmatic donors. Furthermore, in a recent longitudinal study of exacerbation-prone asthmatic children, higher baseline epithelial expression of a T2 gene module and lower expression of an IFN module were associated with a shorter time to viral-triggered exacerbation.

In our cohort of well-characterized asthmatic children, from whom we obtain bronchial AECs and conduct mechanistic ex vivo experiments using organotypic models, we have observed marked heterogeneity in IFN I/III responses to HRV and RSV infection, with greater HRV replication in AECs from exacerbation-prone asthmatics. We recently observed greater production of the T2 alarmins TSLP and IL-33 by asthmatic AECs with the lowest IFN responses to HRV, while AECs with the greatest IFN responses also had the greatest production of T2-LOW/NLRP3 inflammasome-associated cytokines IL-1β and TNF-α. These observations inform our global hypotheses that the magnitude and kinetics of AEC IFN responses to HRV influence T2-HIGH and T2-LOW asthma endotypes, with moderate self-limited IFN responses essential to limit viral replication, reduce exacerbation risk, and dampen T2 inflammation, while exaggerated IFN responses enhance the NLRP3 inflammasome and production of T2-LOW cytokines (IL-1β, TNF-α), neutrophilic inflammation, airway remodeling, and lung function decline.

Furthermore, we hypothesize that a common polymorphism in the viral sensor IFIH1/MDA5 (RS1990760), recently associated with asthma, contributes to dysregulated AEC IFN responses to HRV. Finally, we will use a humanized mouse expressing HICAM1 to allow HRV-A infection, in the context of differential MDA5 function, to test in vivo the role of these pathways in HRV-A infection, T2-HIGH vs. T2-LOW airway inflammation, exacerbation, and airway remodeling.

Seattle Children's Hospital

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]

Washington United States

State-Wide

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

Amendment Since initial award the total obligations have increased 279% from $919,436 to $3,482,387.