R01AI162850

Pulmonary Pathophysiology Sub-Phenotypes of Pneumonia - Pneumonia causes adverse outcomes including hospitalization, intensive care, and death. Host response is pivotal, with immune activities and cell dysfunctions responsible for pathophysiologies including but not limited to excessive microbial growth, alveolar flooding, and septal destruction. Many diverse biological pathways can lead to adverse outcomes within the infected lungs.

A better understanding of the immunological and cellular activities occurring inside severely infected lungs is needed to distinguish sub-phenotypes of disease and improve the development and application of host-directed therapies. In the proposed studies, we will leverage large sets of post-mortem human pneumonic lung samples collected via rapid autopsy for defining pneumonia sub-phenotypes based on their pulmonary pathobiology.

We will integrate semi-quantitative histopathology (scored by board-certified pathologists), quantitative multiplex fluorescent immunohistochemistry (MFIHC; to enumerate and localize immune cells within these lungs), and single nuclei RNA sequencing (snRNA-seq; to broaden and deepen cell and molecular resolution of these lungs) in order to differentiate distinct lung pathobiologies during pneumonia. In addition, we will examine multiple current and emergent experimental models of severe pneumonia to determine which, if any, recapitulate elements of these pulmonary pathobiologies.

We propose to test the central hypothesis that severe pneumonias cluster into distinct lung pathobiology sub-phenotypes by pursuing the following specific aims:

Aim 1) To test whether humans dying with pneumonia segregate into lung pathology sub-phenotypes, using rapid autopsy samples analyzed via histopathologic scoring and quantitative MFIHC.

Aim 2) To validate and elucidate pneumonia sub-phenotypes using an independent cohort with microscopy matched to snRNA-seq for defining cell types and cell-specific gene expression in infected human lungs.

Aim 3) To test whether established and emerging experimental models of severe pneumonia recapitulate some and which elements of human pulmonary pathobiology.

The proposed studies will be significant for generating discoveries from lung and blood samples of pneumonia cases in elderly subjects, an especially high-risk group for pneumonia. Proposed studies will increase resolution into the heterogeneity of pneumonia, a currently pressing research priority. Results will reveal whether sub-phenotypes or select features measured within the pneumonic lungs differ between pneumonias caused by pneumococcus, influenza, and SARS-CoV-2.

Defining subtypes of pneumonia with distinct molecular and cellular changes in the lungs will improve the development and use of host-directed approaches for treating or preventing pneumonia.

Trustees Of Boston 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]

Boston, Massachusetts 021182642 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 276% from $856,279 to $3,223,607.