New research on COPD aims to selectively ‘disarm’ specific pathogens

BUFFALO, N.Y. — For decades, bacterial infections in people suffering from chronic obstructive pulmonary disease (COPD) have been treated primarily with traditional antibiotics. While such drugs can be effective in treating acute infections, they have had little clinical effect on the patient population as a whole: The disease remains the third most common cause of death in the U.S., and death rates have doubled since 1970.

Most commonly caused by smoking, COPD includes chronic bronchitis and emphysema; it compromises the lungs’ innate defense against bacteria, allowing bacteria to persist and causing respiratory symptoms, coughing and sputum production. Current treatments include anti-inflammatory drugs, as well as frequent use of antibiotics.

Now, a University at Buffalo team has received a five-year, $2.7 million National Institutes of Health (NIH) grant aimed at developing a much more precise method of treatment: the selective eradication of specific pathogens in the airways that affect quality of life and lead to the loss of lung function over time.

Highlights of the grant:

• The research includes the study of the pathogen Moraxella catarrhalis (Mcat) in addition to non-typeable Haemophilus influenzae (NTHi), which is the most common COPD pathogen. While Mcat is the second most common cause of bacterial infection in COPD, it is poorly understood and rarely studied; only a handful of labs in the world study Mcat.
• In addition to studying the DNA (the genomes) of the bacteria that cause infections, the scientists will study the RNA that the DNA expresses (the transcriptomes) in order to understand which genes turn on or off during infection.
• Fresh sputum samples of newly enrolled patients will allow the researchers to study the key molecules present in patients’ airways.

This is the 33rd year of continuous NIH funding for the researchers, who are among the world’s top scientists studying COPD. Timothy F. Murphy, MD, SUNY Distinguished Professor and senior associate dean of clinical and translational research at the Jacobs School of Medicine and Biomedical Sciences, and Sanjay Sethi, MD, professor; chief of pulmonary, critical care and sleep medicine at the Jacobs School; division chief of UBMD Internal Medicine; and staff physician at the VA Western New York Healthcare System, have together conducted the longest prospective study of COPD in the world with monthly sampling. The research has broken new ground in understanding how bacterial infections affect patients, and therefore, how best to treat them.

The presence of bacterial pathogens in the lower airways (bronchial passageways) reduces the quality of life for patients and accelerates the loss of lung function, Murphy explained.

“Long-term treatment with antibiotics is not a viable option,” he said, “since they are not effective, they cause adverse effects and lead to resistance. By contrast, the selective eradication or ‘disarming’ of pathogens in the lower airways has great potential as an intervention.”

Both of the pathogens under study, NTHi and Mcat, have evolved mechanisms that allow them to proliferate in the human respiratory tract. “These are exclusively human pathogens,” said Murphy, “so inhibiting key molecules that cause them to persist will ‘tip the balance’ toward clearance.”

He explained that selectively targeting these pathogens has the advantage of leaving undisturbed the respiratory tract microbiome, the bacteria that are present normally and that protect the airways.

“Traditional antibiotics wipe out the normal microbiome, leaving the patient more susceptible to infection and causing unpleasant side effects,” Murphy said. ”Selective eradication of pathogens is an entirely new approach to the problem.”

Murphy and Sethi work closely with Melinda Pettigrew, PhD, of Yale University School of Public Health and Hervé Tettelin of the Institute for Genome Sciences, University of Maryland School of Medicine.