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

Aspergillus fumigatus is a human fungal pathogen that can cause devastating pulmonary 29 infections, termed aspergilloses, in individuals suffering immune imbalances or 30 underlying lung conditions. As rapid adaptation to stress is crucial for the outcome of 31 the host-pathogen interplay, here we investigated the role of the versatile post-32 translational modification persulfidation for both fungal virulence and antifungal host 33 defence. We show that an A. fumigatus mutant with low persulfidation levels is more 34 susceptible to host-mediated killing and displays reduced virulence in murine models of 35 infection. Additionally, we found that a single-nucleotide-polymorphism (SNP) in the 36 human gene encoding cystathionine-γ-lyase causes a reduction in cellular persulfidation 37 and correlates with a predisposition of hematopoietic-stem-cell-transplant recipients to 38 invasive pulmonary aspergillosis, as correct levels of persulfidation are required for 39 optimal antifungal activity of recipients’ lung-resident host cells. Importantly, the levels 40 of host persulfidation determine the levels of fungal persulfidation, ultimately reflecting 41 a host-pathogen functional correlation and highlighting a potential new therapeutic 42 target for the treatment of aspergillosis.