Fungal and host protein persulfidation are functionally correlated and modulate both virulence and antifungal response

This is the final version. Available on open access from the Public Library of Science via the DOI in this recordData Availability: All raw data that support the findings of this study is available in the supplementary figures, tables and datasets.Aspergillus fumigatus is a human fungal pathogen that can cause devastating pulmonary infections, termed “aspergilloses,” in individuals suffering immune imbalances or underlying lung conditions. As rapid adaptation to stress is crucial for the outcome of the host–pathogen interplay, here we investigated the role of the versatile posttranslational modification (PTM) persulfidation for both fungal virulence and antifungal host defense. We show that an A. fumigatus mutant with low persulfidation levels is more susceptible to host-mediated killing and displays reduced virulence in murine models of infection. Additionally, we found that a single nucleotide polymorphism (SNP) in the human gene encoding cystathionine γ-lyase (CTH) causes a reduction in cellular persulfidation and correlates with a predisposition of hematopoietic stem cell transplant recipients to invasive pulmonary aspergillosis (IPA), as correct levels of persulfidation are required for optimal antifungal activity of recipients’ lung resident host cells. Importantly, the levels of host persulfidation determine the levels of fungal persulfidation, ultimately reflecting a host–pathogen functional correlation and highlighting a potential new therapeutic target for the treatment of aspergillosis.Medical Research Council (MRC)National Institute for Health Research (NIHR)National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs)European Regional Development Fund (FEDER)Fundação para a Ciência e TecnologiaDeutsche Forschungsgemeinschaft (DFG)La Science Pour la Santé ATIP AvenirFondation pour la Recherche Médicale (FRM