R01AI174590

Novel mechanisms regulating immunity to respiratory virus infection - Influenza viruses are rapidly mutating RNA viruses and are the causative agent of about one billion annual respiratory virus infections and 500,000 deaths worldwide. Influenza-related deaths are generally attributable to viral or bacterial pneumonia (from secondary bacterial infections); excessive inflammation resulting in acute respiratory distress syndrome; and severe lung immunopathology, leading to hypoxia and multi-organ failure.

Influenza viruses have significant pandemic potential, seasonal epidemics burden the human population, and viral resistance has developed to all available treatment options. Much emphasis is placed on the humoral immune response to influenza, as neutralizing antibodies are the desired vaccine outcome. However, B cell-deficient mice and humans with hyper-IgM syndrome clear influenza virus infections, while T cell-deficient mice do not. Thus, B cell-independent mechanisms protect against influenza virus-related mortality.

However, the immune response to influenza virus infection remains poorly understood, and much-needed therapeutics augmenting the antiviral immune response while preventing harmful immunopathology remain to be developed. To address this knowledge gap, we recently generated novel and compelling evidence that influenza A virus (IAV) infection triggers lung mast cells (MCs) to produce the anti-inflammatory cytokine IL-10 (MC-IL-10).

In wild-type (WT) and T- and B-cell deficient (RAG1-KO) mice, IAV/MC-IL-10 induces the expression of the IL-10 receptor (IL-10R) and programmed cell death ligand 1 (PD-L1) on natural killer (NK) cells. Notably, in RAG1-KO mice, where NK cells are the sole virus-fighting lymphocytes, PD-L1 blockade, but not PD-1, PD-L2, or CD80 blockade, significantly reduces IAV-related lethality.

The IAV/MC-IL10/NK-PD-L1 pathway is also conserved in humans, at least in vitro: IAV infection of human-lung tissue-derived single-primary-cell suspensions or intact human lung tissue slices elicit MC-IL-10 and NK cell-expressed IL-10R and PD-L1. In mice and humans, T cells also upregulate the IL-10R, PD-1, and PD-L1 upon IAV infection.

Further, IAV-infected IL-10-KO/RAG-WT mice, whose NK and T cells do not upregulate IL-10R, PD-1, PD-L1, or PD-L2, and IAV-infected WT mice in which PD-L1 is blocked, develop prolonged immune infiltration and immunopathology after IAV clearance.

Our findings are novel and surprising. The induction of the PD/PD-L pathway is generally associated with lymphocyte exhaustion (via T cell-expressed PD-1) in cancer or chronic infection rather than the modulation of lymphocyte function in response to an acute viral illness. We hypothesize that influenza virus-induced MC-IL-10 balances helpful antiviral responses with harmful immunopathology through PD-L1 signaling in NK cells, and PD-1 and/or PD-L1 signaling in T cells.

We propose identifying the mechanisms of IAV/MC/IL-10/PD-L1-mediated NK cell and IAV/MC/IL-10/PD-1 and/or PD-L1-mediated T cell regulation and each pathway's contribution to viral clearance vs. lung tissue damage. Our proposal is highly significant to human health, as it has great potential to identify therapeutic targets for alleviating IAV immunopathology-associated mortality and morbidity.

Jackson Laboratory

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]

Connecticut United States

State-Wide

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

Amendment Since initial award the End Date has been shortened from 07/31/27 to 07/31/25 and the total obligations have increased 487% from $900,758 to $5,288,417.