By Joseph F. John, Jr., MD

Clinical Professor of Medicine and Microbiology, Medical University of South Carolina, and Lowcountry Infectious Diseases, Charleston

Dr. John reports no financial relationships relevant to this field of study.

SYNOPSIS: This study examines the mechanism that allows Moraxella catarrhalis to persist in some patients with chronic obstructive pulmonary disease.

SOURCE: Murphy TF, Brauer AL, Pettigrew MM, et al. Persistence of Moraxella catarrhalis in chronic obstructive pulmonary disease and regulation of Hag/MID adhesin. J Infect Dis 2019;219:1448-1455.

Dr. Tim Murphy in Buffalo has been working on the microbiology of symptomatic pulmonary disease for many years. Here is the latest and greatest installment from a cohort of adults with chronic obstructive pulmonary disease (COPD) studied prospectively over the past 20 years. Over the years, Dr. Murphy’s multitalented group has discovered that one of the major bacterial pathogens in COPD, Moraxella catarrhalis, has a variability of duration of colonization. What allows this organism to colonize and then persist in some COPD patients and not in others? The reason for the variability heretofore has been unknown. This current explanation in this paper is that one of the major adhesins, Hag/MID, in its expression and then disappearance, explains the persistence of M. catarrhalis.

In the ongoing study from 1994 to 2014, patients with COPD were seen every month. An exacerbation caused by M. catarrhalis was considered to be the onset of new clinical symptoms and the acquisition of a new strain of M. catarrhalis. Investigators studied the genetic characteristics of the Hag/MID gene in persistent and cleared strains. Researchers also studied adherence to human epithelial cells and expression of the Hag/MID protein for the persistent and cleared strains. Earlier studies had shown that Hag/MID mediates adherence of the bacterium to respiratory epithelial cells, one of the virulence phenotypes. When Hag/MID is expressed, the bacterium shows aggregation when grown in BHI broth, a second virulence phenotype.

The major finding of the study was that most strains that expressed Hag/MID on acquisition in COPD patients ultimately lost that expression during persistence. The paper goes on to study the mechanism of the loss of Hag/MID expression. In five persistent strains, the Hag/MID gene had one of two different genetic changes. One was an out of frame mutation, thus, the protein was not expressed. Another mode of dysregulation was caused by slipped-strand misparing through changes in a polynucleotide repeat near the start codon in the open reading frame. The impact of the loss of Hag/MID was studied further with regard to virulence phenotypes. Loss of the protein resulted in decreased adherence to respiratory epithelial cells and loss of aggregation.

COMMENTARY

What is going on here? An adhesion molecule aids a bacterium to inhabit initially an abnormal respiratory tract, perhaps causing a frank exacerbation of bronchitis. Then, for it to persist, it loses the very adhesin that aided its initial colonization. Why does the bacterium even care to make this small genetic change that results in a radical change in protein expression (in this case, a protein that is related to virulence)? The paradox may reside mainly in the concept that pathogens in COPD do not want to kill the host. In the case of the COPD patient, the host houses an immense surface area of respiratory epithelium that offers a sanctuary if the bacterium can reside relatively peacefully. Getting in is the first order for M. catarrhalis, but guaranteed survival in a demanding environment is paramount. Indeed, in the study, Hag/MID continued to be expressed in 28 of 30 strains that were cleared, whereas only 17 of 30 strains that were persistent continued to express the protein. The longer the persistence, the less likely it was that Hag/MID would be expressed. Hag/MID is a multifunctional autotransporter. Why would its persistence be facilitated by its absence?

Hag/MID does elicit an immune response, both mucosal and systemic. Perhaps these responses select the Hag/MID-negative phenotype, allowing the organism to escape some immune control. Analogously, there are prospects for immunization with Hag/MID. Vaccines may reduce initial colonization with M. catarrhalis, an apparent advantage for the COPD patient. Enter the airway microbiome, the last consideration in this paper. Clearly, compared to the airway microbiome in healthy people, the airway microbiome in COPD patients contains several pathogens, including M. catarrhalis. Even the COPD airway has to come to some equilibrium, and in that sense, the downregulation of Hag/MID serves an equilibrium of the microbiome even in the altered pulmonary airway.

This work by Murphy et al, a composite over many years using a most cooperative COPD cohort, shows the complexity of the bacterial pathogens’ flux into and out of the pulmonary environment. One of these pathogens, M. catarrhalis, is well armed to invade this environment, but once there, is happy to downregulate its virulence. This research group may have discovered a trait of some pathogens to invade but, once established in a milieu, to use genetic mechanisms to modify its protein expression to become part of the microbial background.