Do All Cystic Fibrosis Modulators Improve Killing of Bacteria?

February 12, 2019
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Treated immune cells function properly to kill more bacteria, depending on the treatment and the bacteria.

Ivacaftor-treated patients with cystic fibrosis (CF) have improved macrophage-mediated bacterial killing, whereas patients treated with lumacaftor/ivacaftor do not, according to a new study published in Scientific Reports.

Physicians and researchers led by Benjamin Kopp, MD, MPH, of the Division of Pulmonary Medicine at Nationwide Children’s Hospital, characterized macrophage responses to clinical cystic fibrosis transmembrane conductance regulator (CFTR) modulator treatments and hypothesized that the effects of the treatments on macrophage function would depend upon patient genotype.

“We’ve learned over time that CF is a relative immunodeficiency,” says Dr. Kopp. “It’s important to take a personalized approach to understand how therapies might differ from patient to patient and how each therapy might differentially affect immune function.”

The study included 37 patients with CF and 42 age- and gender-matched healthy controls. CF patients with the Class II CFTR genotypes (n=27, 73%) took lumacaftor/ivacaftor, while those with the Class III/IV/V CFTR genotypes (n=10, 27%) took ivacaftor alone.

The team demonstrated that monocyte-derived macrophages from CF patients treated in vitro with ivacaftor had a restoration of phagocytosis of fluorescent beads and non-virulent Burkholderia cenocepacia bacteria comparable to the levels of non-CF macrophages, whereas those treated with lumacaftor/ivacaftor did not and even trended toward decreased phagocytosis.

Next, the researchers measured bacterial loads of three virulent strains: B. cenocepacia, methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa. Patients with CF, taking CFTR modulators or not, did not have significant differences in bacterial loads of B. cenocepacia and MRSA. However, P. aeruginosa bacterial load was reduced by 89% in ivacaftor-treated patients and was non-significantly decreased in lumacaftor/ivacaftor-treated patients, suggesting that CFTR modulators differentially enhance bacterial killing.

Further characterization revealed that CFTR expression increased in macrophages from patients with CF taking ivacaftor compared to lumacaftor/ivacaftor or untreated patients with CF, but did not achieve non-CF levels. While ivacaftor reduced levels of macrophage apoptosis to non-CF levels, macrophages from patients taking lumacaftor/ivacaftor showed a non-significant decrease. These findings suggest that CFTR expression helps regulate macrophage stability, and by increasing CFTR expression, CFTR modulators increase macrophage survival.

“We know a variety of macrophage functions are impaired, but we still don’t fully understand how CFTR regulates these processes in immune cells. That’s a major question in the field,” says Dr. Kopp, who is also a Principal Investigator in the Center for Microbial Pathogenesis. “There’s still a lot to understand about the biology of CFTR and how [CFTR modulator] therapies can influence immune function.”

The authors noted that most of the experiments were conducted using monocyte-derived macrophages, whose response may differ from alveolar macrophages. Additionally, other immune cells may be needed for complete bacterial killing in vivo.

“Chronic infection is still something we must aggressively deal with and treat in [CF] patients. Despite some of the improvements we saw in macrophage function, specifically with patients on ivacaftor, it didn’t quite get to the level of bacterial clearance that we might have expected,” says Dr. Kopp.  “The CFTR modulators certainly are not fully correcting that aspect of immune function in CF [patients]. Physicians should still be cautious managing infection in these patients.”

“This is an emerging field, and it is going to be a multi-disciplinary team effort to understand how new therapies impact immune function in our patients.”


Zhang S, Shrestha CL, Kopp BT. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have differential effects on cystic fibrosis macrophage function. Scientific Reports. 2018; 8(1):17066.

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