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BTK drives neutrophil activation for sterilizing antifungal immunity

Summary

BTK is a protein that helps neutrophils (immune cells) fight fungal infections, particularly Aspergillus fumigatus. A cancer drug called ibrutinib blocks BTK, which weakens neutrophil antifungal responses and increases the risk of serious fungal infections. The study found that GM-CSF may help restore some immune function in patients taking BTK-blocking drugs, offering a potential strategy to prevent these dangerous infections.

Background

Bruton’s tyrosine kinase (BTK) is critical for B-cell receptor signaling and B-cell function. Ibrutinib, an irreversible BTK inhibitor used to treat B-cell malignancies, has been associated with increased risk for invasive aspergillosis. This study investigates BTK-dependent fungal responses in neutrophils to understand susceptibility in ibrutinib-treated patients.

Objective

To elucidate the role of BTK in neutrophil-mediated antifungal immunity against Aspergillus fumigatus and explain the increased susceptibility to invasive aspergillosis in BTK inhibitor-treated patients.

Results

BTK activation in neutrophils in response to Aspergillus was TLR2-, Dectin-1-, and FcγR-dependent, leading to oxidative burst. BTK inhibition impaired neutrophil capacity to damage hyphae and induce oxidative burst by blocking p40 phox and RAC2 activation. GM-CSF partially mitigated these defects through p47 phox activation, and the BTK rs5951308 polymorphism was associated with increased invasive aspergillosis risk.

Conclusion

BTK plays a previously unappreciated role in neutrophil-mediated fungal immune surveillance against Aspergillus fumigatus, explaining the increased aspergillosis risk in ibrutinib-treated patients. GM-CSF may support immune function in susceptible patients with BTK inhibition.
  • Published in:Open Forum Infectious Diseases,
  • Study Type:Basic and translational research study,
  • Source: 10.1093/ofid/ofae631.1243; PMC11777694
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