Fungal and host protein persulfidation are functionally correlated and modulate both virulence and antifungal response.
A549 Cells
Adult
Animals
Antifungal Agents
/ pharmacology
Aspergillosis
/ epidemiology
Aspergillus fumigatus
/ drug effects
Cystathionine gamma-Lyase
/ genetics
Epithelial Cells
/ drug effects
Female
Fungal Proteins
/ metabolism
Hematopoietic Stem Cell Transplantation
/ adverse effects
Host-Pathogen Interactions
/ drug effects
Humans
Incidence
Macrophages, Alveolar
/ drug effects
Male
Mice, Inbred C57BL
Oxidative Stress
/ drug effects
Polymorphism, Single Nucleotide
/ genetics
Sulfides
/ metabolism
THP-1 Cells
Transplant Recipients
Virulence
/ drug effects
Young Adult
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
02
06
2020
accepted:
27
04
2021
entrez:
1
6
2021
pubmed:
2
6
2021
medline:
29
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34061822
doi: 10.1371/journal.pbio.3001247
pii: PBIOLOGY-D-20-01613
pmc: PMC8168846
doi:
Substances chimiques
Antifungal Agents
0
Fungal Proteins
0
Sulfides
0
Cystathionine gamma-Lyase
EC 4.4.1.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3001247Subventions
Organisme : Medical Research Council
ID : G0501164
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V033417/1
Pays : United Kingdom
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/P002390/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N006364/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M02010X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N008707/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Déclaration de conflit d'intérêts
I have read the journal’s policy and the authors of this manuscript have the following competing interests. In the past 5 years SG has received research funds from Pfizer and has been a council member of the International Society of Human and Animal Mycology (ISHAM). All other authors declare no conflicts of interest.
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