Medical Professional Publications

Why Some Bacterial Infections in Cystic Fibrosis Patients are Hard to Clear

Columbus, OH — March 2017

Patients with cystic fibrosis (CF) are prone to chronic, multidrug-resistant bacterial infections. To develop new therapies, it is crucial to figure out how bacteria avoid immune defenses in CF — especially given the shortage of development of new antimicrobials and increasing antibiotic resistance worldwide.

Benjamin Kopp, MD — a pediatric pulmonologist and principal investigator in the Center for Microbial Pathogenesis at The Research Institute at Nationwide Children’s Hospital — and colleagues recently discovered a novel defective pathway in CF immune cells. The research is published in the January 2017 issue of the Journal of Immunology.

A hallmark of CF is chronic bacterial infections in the sinuses and respiratory tract. These are part of a vicious cycle of infection and inflammation that causes chronic lung damage and leads to the majority of the morbidity and mortality associated with CF.

“The long-standing dogma was that CF patients produce this thick mucus and they are subsequently unable to clear bacteria,” says Dr. Kopp, who is also an assistant professor of Pediatrics at The Ohio State University College of Medicine. “But that’s just a part of the puzzle. More recently we’ve grown to recognize there are actually issues with how immune cells interact with bacteria in CF, as well.”

One of the first responses of the body to infection is the generation of reactive oxygen species (ROS) via assembly of the NADPH oxidase within immune cells called macrophages. In CF, this oxidative burst is defective, and macrophages do not kill pathogens effectively, creating a niche for bacterial replication.

Dr. Kopp and his colleagues characterized the responses of CF macrophages to an antibiotic-resistant pathogen, Burkholderiacenocepacia, which is particularly virulent in CF patients.

They found that macrophages from CF patients have an inherent reduction in ROS production that is worsened by bacteria like B. cenocepacia. The deficit is due to problems in the assembly of the NADPH oxidase within the macrophages.

The findings, which implicate a critical role for defective macrophage oxidative responses in persistent bacterial infections in patients with CF, may lead to the identification of new targets for drug development. For instance, Burkholderia and other chronic infections in CF could be treated by boosting the performance of macrophages.

“There is evidence that the immune system is altered very early on in CF,” says Dr. Kopp. “The more you can prevent the establishment of chronic infections, perhaps with therapeutics to augment the immune system, the better off patients will be.”

Dr. Kopp says the next step is screening chemicals in the laboratory to search for compounds that can reverse the deficits in CF macrophages.

“We are still probably a few years away from these results being translated into a relevant therapeutic,” says Dr. Kopp.

“It’s about trying to change the paradigm of how we treat infections in CF. Future treatments could be synergistic with antibiotics, or they could do away with the need for antibiotics, if they could help patients mount an effective immune response and prevent chronic infections.”

Reference:
Assani K., Shrestha C. L., Robledo-Avila F., Rajaram M. V., Partida-Sanchez S., Schlesinger L. S. and Kopp B. T. (2017). Human cystic fibrosis macrophages have defective calcium-dependent protein kinase C activation of the NADPH oxidase, an effect augmented by Burkholderia cenocepacia. Journal of Immunology. 2017 Jan 16. [Epub ahead of print]

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