Virulent Pseudomonas aeruginosa infection converts antimicrobial amyloids into cytotoxic prions.
Amyloid
/ chemistry
Animals
Anti-Bacterial Agents
/ pharmacology
Bacterial Proteins
/ immunology
Cytotoxins
/ pharmacology
Endothelial Cells
/ drug effects
Female
Host-Pathogen Interactions
Humans
Lung
/ drug effects
Male
Prions
/ pharmacology
Pseudomonas Infections
/ drug therapy
Pseudomonas aeruginosa
/ isolation & purification
Rats
Rats, Inbred F344
Rats, Sprague-Dawley
Virulence
/ drug effects
amyloid beta (Aβ)
exoenzyme Y (ExoY)
nosocomial pneumonia
prion
tau (τ)
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
07
01
2020
revised:
19
04
2020
accepted:
21
04
2020
pubmed:
16
5
2020
medline:
5
3
2021
entrez:
16
5
2020
Statut:
ppublish
Résumé
Pseudomonas aeruginosa infection elicits the production of cytotoxic amyloids from lung endothelium, yet molecular mechanisms of host-pathogen interaction that underlie the amyloid production are not well understood. We examined the importance of type III secretion system (T3SS) effectors in the production of cytotoxic amyloids. P aeruginosa possessing a functional T3SS and effectors induced the production and release of cytotoxic amyloids from lung endothelium, including beta amyloid, and tau. T3SS effector intoxication was sufficient to generate cytotoxic amyloid release, yet intoxication with exoenzyme Y (ExoY) alone or together with exoenzymes S and T (ExoS/T/Y) generated the most virulent amyloids. Infection with lab and clinical strains engendered cytotoxic amyloids that were capable of being propagated in endothelial cell culture and passed to naïve cells, indicative of a prion strain. Conversely, T3SS-incompetent P aeruginosa infection produced non-cytotoxic amyloids with antimicrobial properties. These findings provide evidence that (1) endothelial intoxication with ExoY is sufficient to elicit self-propagating amyloid cytotoxins during infection, (2) pulmonary endothelium contributes to innate immunity by generating antimicrobial amyloids in response to bacterial infection, and (3) ExoY contributes to the virulence arsenal of P aeruginosa through the subversion of endothelial amyloid host-defense to promote a lung endothelial-derived cytotoxic proteinopathy.
Identifiants
pubmed: 32413239
doi: 10.1096/fj.202000051RRR
pmc: PMC7383673
mid: NIHMS1599061
doi:
Substances chimiques
Amyloid
0
Anti-Bacterial Agents
0
Bacterial Proteins
0
Cytotoxins
0
Prions
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9156-9179Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL135003
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL076125
Pays : United States
Organisme : NHLBI NIH HHS
ID : K25 HL136869
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL118334
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL140182
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI104922
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL147512
Pays : United States
Organisme : NHLBI NIH HHS
ID : R37 HL060024
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL060024
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL066299
Pays : United States
Informations de copyright
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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