作者
Jigar V. Desai,Marissa A. Zarakas,Andrew Wishart,Mark Roschewski,Mariano A. Aufiero,Ágnes Donkó,Gustaf Wigerblad,Tobias M. Hohl,Markus Plate,Matthew R. James,Jean K. Lim,Gülbû Uzel,Jenna Bergerson,Ivan J. Fuss,Robert A. Cramer,Luis M. Franco,Emily Clark,Wasif N. Khan,Daisuke Yamanaka,Georgios Chamilos,Jamel El Benna,Mariana J. Kaplan,Louis M. Staudt,Thomas L. Leto,Steven M. Holland,Wyndham H. Wilson,Tobias M. Hohl,Michail S. Lionakis
摘要
We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.