# Genome Evolution During Bacterial Persistence in the Human Airways in COPD

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $537,008

## Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic debilitating disease that afflicts ~24 million
Americans and is the fourth leading cause of death in the US and in the world. The lower airway microbiome of
adults with COPD harbors bacterial pathogens that are absent in the lower airway microbiome of healthy
people. In rigorous prospective studies, nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis
(Mcat) are by far the most common bacterial pathogens that persist in the lower airways in COPD. The
presence of these pathogens in the lower airways has profound consequences on the clinical course and
pathogenesis of the disease. Persistent bacteria induce airway inflammation that results in increased
symptoms, enormous morbidity, and also leads to acceleration of the progressive loss of lung function that
leads to early mortality in COPD. Our work over the last five years has provided key observations to guide the
work proposed here to advance the field by identifying mechanisms by which these exclusively human
pathogens persist in the unique environment of COPD airways. For example, while NTHi and Mcat are
classically considered to be extracellular pathogens, multiple lines of evidence now show that both pathogens
invade and survive in human respiratory epithelial cells and macrophages, resulting in a reservoir of
intracellular bacteria that resist clearance by antibiotics and host mechanisms. In aim 1, we will elucidate the
evolutionary dynamics of bacterial pathogens in the natural environment of the human COPD airways by
analyzing the genomes of serial isolates of strains of NTHi and Mcat that have persisted for months to years. In
aim 2, we will examine transcriptional profiles of serial isolates of persistent strains and transcripts from fresh
sputum samples collected from adults with COPD with persistent NTHi and Mcat to identify gene products that
undergo changes that enable persistence in COPD airways. In Aim 3, guided by dynamic changes in genomes
and transcriptomes in human airways, we will elucidate mechanisms that mediate persistence of NTHi and
Mcat using relevant model systems. This work will lead directly to an innovative approach of identifying specific
targets for intervention through pathogen-specific eradication and/or anti-virulence antimicrobial agents, which
would leave the normal microbiota undisturbed. This approach has far-reaching clinical benefits, representing a
completely novel approach to treating bacterial infection in COPD, which has relied on traditional antibiotics for
70 years.

## Key facts

- **NIH application ID:** 9969294
- **Project number:** 5R01AI019641-34
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Timothy F Murphy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $537,008
- **Award type:** 5
- **Project period:** 1983-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969294

## Citation

> US National Institutes of Health, RePORTER application 9969294, Genome Evolution During Bacterial Persistence in the Human Airways in COPD (5R01AI019641-34). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9969294. Licensed CC0.

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