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Principal Investigator: JOSEPH P MIZGERD
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $805,021
Funding agency: National Institute of Allergy and Infectious Diseases
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 sub-types 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.
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