Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model.
Animals
Bacteremia
/ metabolism
Bacterial Adhesion
Disease Models, Animal
Endothelial Cells
Female
Fimbriae Proteins
/ genetics
Fimbriae, Bacterial
/ physiology
Humans
Meningococcal Infections
/ metabolism
Mice
Mice, SCID
Neisseria meningitidis
/ pathogenicity
Sepsis
/ metabolism
Skin Transplantation
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
28
09
2020
accepted:
11
01
2021
revised:
26
02
2021
pubmed:
17
2
2021
medline:
24
6
2021
entrez:
16
2
2021
Statut:
epublish
Résumé
Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis.
Identifiants
pubmed: 33592056
doi: 10.1371/journal.ppat.1009299
pii: PPATHOGENS-D-20-02134
pmc: PMC7909687
doi:
Substances chimiques
Fimbriae Proteins
147680-16-8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009299Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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