Abstract
Abstract Background Bruton’s tyrosine kinase (BTK) is a critical component of B-cell receptor signaling and regulates B-cell proliferation and survival. Ibrutinib is an irreversible inhibitor of BTK and is successfully used in treatment of various B-cell malignancies. However, it has been associated with increased risk for invasive aspergillosis (IA). Model of BTK-dependent responses promoting neutrophil activation in response to Aspergillus fumigatus. Methods To shed light in the susceptibility of ibrutinib-treated patients, we studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Results In response to fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, leading to oxidative burst. BTK inhibition selectively impaired neutrophils’ capacity to damage Aspergillus hyphae, release primary granules and induce oxidative burst by impeding the activation of NADPH oxidase subunit p40phox and GTPase RAC2. Similarly, we found impaired neutrophil function in Aspergillus-infected, neutrophil-specific Btk deficient mice, whereas neutrophil recruitment and survival were spared. These defects were partially mitigated by GM-CSF via enhancing p47phox activation, supporting a role for GM-CSF use in susceptible patients. The presence of the BTK rs5951308 (T >C; E24G) in donors of allogeneic hematopoietic transplant recipients was independently associated with increased risk of IA. Conclusion Our data uncover a previously unappreciated role for BTK in fungal immune surveillance against Aspergillus fumigatus. Disclosures All Authors: No reported disclosures
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call