Abstract
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.
Highlights
Posttranslational modifications (PTMs) constitute a rapidly acting response mechanism that permits fast adaptation to short-lasting and varying stresses
Reduced protein persulfidation in A. fumigatus is correlated with decreased virulence, as we show that this PTM modulates peroxiredoxin and alcohol dehydrogenase activities, which are known to be relevant for fungal pathogenicity
MecB and MecA are highly similar to their human counterparts (MecB 53% identity, 69% similarity; MecA 54% identity, 69% similarity) indicating a conserved activity, while MstA has a lower similarity rate (37% identity, 51% similarity), suggesting the potential of having an analogous function
Summary
Posttranslational modifications (PTMs) constitute a rapidly acting response mechanism that permits fast adaptation to short-lasting and varying stresses. It has been postulated that H2S exerts its signaling via protein persulfidation [5], a PTM that consists of the conversion of a thiol (−SH) into a persulfide (–SSH) group in cysteine residues of target proteins [6]. The exact mechanism by which H2S becomes activated to modify targeted cysteine residues remains unclear [7]. Persulfidation can increase or decrease the function or activity of a given protein, which translates into a prominent regulatory role for various physiological functions [8], including inflammation and counteracting endoplasmic reticulum stress [5]. Despite evidence of its importance, little is known about the role and relevance of protein persulfidation in immune responses to pathogen challenge
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