The research team, based at The Ohio State University and Nationwide Children’s Hospital, investigated the innate immune response to Mycobacterium abscessus using peripheral blood monocytes and monocyte-derived macrophages obtained from people with cystic fibrosis and from healthy donors. In the laboratory, the macrophages were infected with opsonized smooth or rough isolates of the bacterium at a low multiplicity of infection. After extracellular bacteria were removed, the researchers measured intracellular bacterial burden, oxidative burst activity, activation of the NOX2 enzyme complex, and cytokine production at two hours and twenty-four hours after infection.

The first key observation concerned bacterial uptake. The amount of Mycobacterium abscessus taken in by the macrophages was comparable across all groups, indicating that the initial engulfment of the bacteria was not the problem. Non-cystic fibrosis macrophages showed no difference in their intracellular burden of either the rough or the smooth morphotype at twenty-four hours.

In sharp contrast, macrophages from people with cystic fibrosis harbored significantly more intracellular rough-morphotype bacteria at the twenty-four-hour time point, suggesting that these cells failed to kill or restrain the virulent form after taking it up. To test whether the cystic fibrosis transmembrane conductance regulator, the protein defective in the disease, was directly responsible, the researchers performed CFTR knockdown in macrophages from healthy donors. This manipulation recapitulated the phenotype seen in the patient-derived cells, with the knockdown macrophages also accumulating more intracellular rough-morphotype bacteria.

A complementary experiment pointed in the same direction: when non-cystic fibrosis macrophages were treated with a CFTR inhibitor, they mimicked the reduced oxidative burst observed in the patient cells. Together, these results link the loss of functional CFTR to the defective bacterial control. The study also identified a specific defect in the respiratory burst machinery.

Macrophages from people with cystic fibrosis that were infected with Mycobacterium abscessus demonstrated a significantly reduced oxidative burst, the rapid production of reactive oxygen species that macrophages use to kill engulfed microbes. At the molecular level, this correlated with diminished phosphorylation of p47phox, a regulatory component of the NOX2 NADPH oxidase complex. Because the oxidative burst is a central antimicrobial weapon of macrophages, its impairment provides a plausible mechanistic explanation for the persistence of intracellular bacteria.

Cytokine signaling was similarly disturbed. Infected cystic fibrosis macrophages exhibited an altered inflammatory profile, with significantly elevated secretion of IL-8, a chemokine that recruits neutrophils, but decreased IL-1β relative to macrophages from healthy donors. The rough morphotype, which is associated with more virulent and persistent infections, produced the most striking differences.

Macrophages from people with cystic fibrosis that were infected with the rough isolate secreted significantly less TNF-α, another key inflammatory cytokine, compared with non-cystic fibrosis macrophages. They also exhibited markedly reduced apoptosis, the programmed cell death process that can help limit intracellular pathogens, compared with both rough-infected non-cystic fibrosis macrophages and smooth-infected cystic fibrosis macrophages.

Taken together, the authors conclude that macrophages from people with cystic fibrosis are intrinsically impaired in their ability to control the virulent rough morphotype of Mycobacterium abscessus. The defects span multiple arms of the macrophage response: bacterial killing, oxidative burst and NOX2 activation, cytokine balance, and apoptosis. Because the study was conducted in cells derived from peripheral blood rather than lung tissue, and at defined early time points after infection in vitro, the findings describe cellular mechanisms rather than clinical outcomes.

Even so, they highlight a potential mechanism for persistent nontuberculous mycobacterial infection in cystic fibrosis and reinforce the argument, made by the researchers, that host-directed therapies deserve attention as a complement to antibiotics against these notoriously drug-resistant organisms.

Subject of Research: Impaired macrophage immune responses to Mycobacterium abscessus infection in cystic fibrosis

Article Title: Mycobacterium abscessus induces immune suppression in cystic fibrosis macrophages

Article References: Hill, P., Miller, C., Rascon, R., Clary, G., Idosa, A., Gavrilin, M. A., McCoy, K., Amer, A. O., Partida Sanchez, S., Kopp, B. T., & Hall-Stoodley, L. (2026). Mycobacterium abscessus Induces Immune Suppression in Cystic Fibrosis Macrophages. Frontiers in Cellular and Infection Microbiology, 16, 1903803. https://doi.org/10.3389/fcimb.2026.1903803

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1903803

Keywords: cystic fibrosis, Mycobacterium abscessus, macrophages, nontuberculous mycobacteria, CFTR, oxidative burst, NOX2, cytokines, innate immunity, host-directed therapy, Mycobacterium, abscessus