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.
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. Persistence of nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) in the lower airways of adults with COPD has profound consequences on the clinical course and pathogenesis of the disease. The work proposed here will elucidate mechanisms of persistence by NTHi and Mcat in the unique environment of the human respiratory tract, leading to an innovative approach of identifying specific targets to achieve pathogen-specific eradication, a completely novel approach to treating COPD.
|Pettigrew, Melinda M; Ahearn, Christian P; Gent, Janneane F et al. (2018) Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A 115:E3256-E3265|
|Jacobs, David M; Ochs-Balcom, Heather M; Zhao, Jiwei et al. (2018) Lower Airway Bacterial Colonization Patterns and Species-Specific Interactions in Chronic Obstructive Pulmonary Disease. J Clin Microbiol 56:|
|Tsuji, Brian T; Fisher, James; Boadi-Yeboah, Raheal et al. (2018) Azithromycin Pharmacodynamics against Persistent Haemophilus influenzae in Chronic Obstructive Pulmonary Disease. Antimicrob Agents Chemother 62:|
|Gallo, Mary C; Kirkham, Charmaine; Eng, Samantha et al. (2018) Changes in IgA Protease Expression Are Conferred by Changes in Genomes during Persistent Infection by Nontypeable Haemophilus influenzae in Chronic Obstructive Pulmonary Disease. Infect Immun 86:|
|Otsuka, Taketo; Brauer, Aimee L; Kirkham, Charmaine et al. (2017) Antimicrobial activity of antisense peptide-peptide nucleic acid conjugates against non-typeable Haemophilus influenzae in planktonic and biofilm forms. J Antimicrob Chemother 72:137-144|
|Ahearn, Christian P; Gallo, Mary C; Murphy, Timothy F (2017) Insights on persistent airway infection by non-typeable Haemophilus influenzae in chronic obstructive pulmonary disease. Pathog Dis 75:|
|Pettigrew, Melinda M; Alderson, Mark R; Bakaletz, Lauren O et al. (2017) Panel 6: Vaccines. Otolaryngol Head Neck Surg 156:S76-S87|
|Murphy, Timothy F; Kirkham, Charmaine; Gallo, Mary C et al. (2017) Immunoglobulin A Protease Variants Facilitate Intracellular Survival in Epithelial Cells By Nontypeable Haemophilus influenzae That Persist in the Human Respiratory Tract in Chronic Obstructive Pulmonary Disease. J Infect Dis 216:1295-1302|
|Post, Deborah M B; Ketterer, Margaret R; Coffin, Jeremy E et al. (2016) Comparative Analyses of the Lipooligosaccharides from Nontypeable Haemophilus influenzae and Haemophilus haemolyticus Show Differences in Sialic Acid and Phosphorylcholine Modifications. Infect Immun 84:765-74|
|Hu, Fang; Rishishwar, Lavanya; Sivadas, Ambily et al. (2016) Comparative Genomic Analysis of Haemophilus haemolyticus and Nontypeable Haemophilus influenzae and a New Testing Scheme for Their Discrimination. J Clin Microbiol 54:3010-3017|
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