A functional polymorphism in IL-36β modulates macrophage antifungal effector functions and increases susceptibility to invasive pulmonary Aspergillosis

Abstract

Background: Genetic predisposition plays a major role in the development of invasive pulmonary aspergillosis (IPA). The risk and course of IPA vary significantly among patients, yet continuously new genetic mechanisms that influence individual antifungal immune responses are being discovered. While genetic variability in interleukin (IL)-1 family cytokines is recognized as an important cause of disease susceptibility, it is unclear whether and how less-studied IL-1 family members, such as the IL-36 cytokine subfamily, are genetically regulated and influence the risk of infection.

Methods: We analyzed how genetic variants in the IL36 loci associate with the risk of IPA in 328 eligible recipients of allogeneic hematopoietic stem cell transplants and their corresponding donors. The functional consequences of relevant genetic variants were investigated using clinical samples and in vitro infection models.

Results: We report that recipient, but not donor, single-nucleotide polymorphisms (SNPs) rs895497 in IL36A and rs4849142 in IL36B increase the risk of IPA after transplantation. The strongest contribution of these SNPs to infection risk was observed in a combined analysis of transplant pairs. IL-36β was expressed in both human type II-like alveolar epithelial cells and macrophages following Aspergillus fumigatus infection. The risk genotype was associated with impaired production of IL-1β in bronchoalveolar lavage fluid samples from infected patients, as well as in fungal-stimulated macrophages. Moreover, macrophages harboring the risk genotype exhibited impaired fungicidal activity.

Conclusions: Our findings suggest that genotype-specific mechanisms mediated by IL-36β act on the nonhematopoietic compartment, can impair antifungal immune responses in macrophages, and ultimately predispose to transplant recipient susceptibility to IPA.