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

PLoS Biol. 2021 Jun 1;19(6):e3001247. doi: 10.1371/journal.pbio.3001247. eCollection 2021 Jun.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adult
  • Animals
  • Antifungal Agents / pharmacology*
  • Aspergillosis / epidemiology
  • Aspergillosis / genetics
  • Aspergillosis / microbiology
  • Aspergillus fumigatus / drug effects
  • Aspergillus fumigatus / enzymology
  • Aspergillus fumigatus / pathogenicity*
  • Cystathionine gamma-Lyase / genetics
  • Epithelial Cells / drug effects
  • Epithelial Cells / microbiology
  • Female
  • Fungal Proteins / metabolism*
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Host-Pathogen Interactions* / drug effects
  • Humans
  • Incidence
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / microbiology
  • Male
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Polymorphism, Single Nucleotide / genetics
  • Sulfides / metabolism*
  • THP-1 Cells
  • Transplant Recipients
  • Virulence / drug effects
  • Young Adult


  • Antifungal Agents
  • Fungal Proteins
  • Sulfides
  • Cystathionine gamma-Lyase