# Sub-phenotyping pneumonia by lung pathobiology

> **NIH NIH F32** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $63,970

## Abstract

Project Summary
 Pneumonia induces heterogeneous responses in the lung, resulting in pathobiological sub-
phenotypes. Because these sub-phenotypes are difficult to identify in patients and are responsive to
different treatments, elucidating and characterizing lung pathology sub-phenotypes is a major research
priority. Mouse models used to study pneumonia may capture some, but not all, human pneumonia
sub-phenotype features, but this has yet to be formally examined. To characterize the lung biology
underlying human pneumonia sub-phenotypes, we analyzed autopsy tissue samples from hundreds of
elderly subjects who died with pneumonia using histopathology and immunohistochemistry. We
observed broad heterogeneous lung pathobiologies and diverse immune landscapes across these
human lung samples, including differences in lymphocyte and neutrophil infiltration. Increased fibrin in
the lung parenchyma positively correlated with neutrophil infiltration, suggesting a link between fibrin
accumulation and neutrophil recruitment or activity. To determine which aspects of human pneumonia
sub-phenotypes are recapitulated or missed in commonly used mouse models of pneumonia, we
characterized pulmonary histopathology in mice with severe and diverse pneumonias caused by
Streptococcus pneumoniae (Sp) or influenza A virus (IAV) infection. IAV infection was characterized by
pulmonary lymphoplasmacytosis, whereas Sp3-infected lungs were instead inundated with neutrophils
and high intra-alveolar fibrin deposition reflecting the fibrin-neutrophil association observed in human
autopsy samples. To investigate the mechanisms promoting pneumonia sub-phenotype diversity in the
lung, we propose in this F32 the following aims to test the hypotheses that 1) age, previous infection
experience, and additional pathogens will reveal additional and diverse pneumonia sub-phenotypes
reflected in our human pneumonia samples, and 2) severing the interactions between polymerized fibrin
and neutrophils in the airspace will decrease the pathogenesis of pneumonia mediated by Sp but not
IAV. Advancing pneumonia models to better reflect human lung biology will help define mechanisms
for the establishment of specific pneumonia sub-phenotypes and will be essential for targeted design
and proper utilization of host-directed pneumonia therapeutics.

## Key facts

- **NIH application ID:** 10934340
- **Project number:** 5F32HL170650-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Bradley Hiller
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $63,970
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934340

## Citation

> US National Institutes of Health, RePORTER application 10934340, Sub-phenotyping pneumonia by lung pathobiology (5F32HL170650-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10934340. Licensed CC0.

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