R37AI093808

Initiation of the immune response to Aspergillus fumigatus - project summary

Invasive aspergillosis is devastating fungal infection and the most common form of mold pneumonia worldwide, with an estimated 200,000 cases annually. Aspergillus fumigatus, the most common etiologic agent of invasive aspergillosis, forms ubiquitous airborne spores that humans inhaled on a daily basis.

In immune competent individuals, the respiratory innate immune system prevents the formation of tissue-invasive hyphae, a critical immunologic checkpoint. In patients with hematologic malignancies, in bone marrow and lung transplant recipients, and recently, in intensive care unit patients with COVID-19, numeric or functional defects in innate immune function lead to invasive disease.

Despite contemporary antifungal drugs, mortality rates remain at 20-40% in high-risk groups, underscoring the need for improved understanding of the molecular and cellular basis of sterilizing immunity to advance immune-based adjunctive approaches.

In the second funding period, we harnessed a fungal bioreporter that reports the mode of cell death to discover that neutrophils and monocyte-derived dendritic cells induce a regulated cell death in engulfed fungal cells. The concept that a higher eukaryote can exploit a regulated cell death machinery in a lower eukaryote is novel and, in the case of A. fumigatus, depends on host NADPH oxidase activity.

NADPH oxidase-dependent fungal killing is modulated by two novel, essential intercellular crosstalk circuits that involve the early production of GM-CSF (GM-CSF circuit) and plasmacytoid dendritic cells (PDC circuit).

During the next project period, we propose to gain a deeper understanding of the GM-CSF and PDC circuits. In Aim 1, we identify the essential cellular source of GM-CSF and, based on preliminary data, focus on pulmonary endothelial and epithelial cells as regulators of neutrophil-dependent fungal killing.

In Aim 2, we define the PDC circuit and candidate transmitters and test models of direct or indirect activation by fungal cells or the lung inflammatory milieu. In Aim 3, we define the mechanisms by which the PDC circuit regulates neutrophils and test its role in NADPH oxidase assembly, activation, and neutrophil metabolism via the pentose phosphate pathway and its cooperativity with the GM-CSF circuit to mediate sterilizing immunity.

The proposed studies are significant and innovative because they integrate innate immune crosstalk between the pulmonary endothelial, epithelial, and PDC compartments and infected myeloid phagocytes into a comprehensive model of respiratory immunity against mold pathogens.

Understanding the induction, regulation, and participants of innate immune crosstalk addresses a critical knowledge gap that will inform immune-enhancing strategies in vulnerable patient groups.

Sloan-Kettering Institute For Cancer Research

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]

New York, New York 100656007 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 398% from $678,475 to $3,376,507.