Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle.
Adaptation, Physiological
Amino Acid Sequence
Animals
Bacterial Proteins
/ genetics
Cell Membrane
/ microbiology
Cholesterol
/ metabolism
Cytoplasm
/ microbiology
Female
Humans
Inflammation
/ microbiology
Loss of Function Mutation
Mice
Models, Structural
Perforin
/ genetics
Pneumococcal Infections
/ microbiology
Sequence Alignment
Streptococcus pneumoniae
/ genetics
Streptolysins
/ genetics
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
17
06
2020
accepted:
24
09
2020
revised:
04
12
2020
pubmed:
21
11
2020
medline:
9
2
2021
entrez:
20
11
2020
Statut:
epublish
Résumé
The opportunistic pathogen Streptococcus pneumoniae has dual lifestyles: one of an asymptomatic colonizer in the human nasopharynx and the other of a deadly pathogen invading sterile host compartments. The latter triggers an overwhelming inflammatory response, partly driven via pore forming activity of the cholesterol dependent cytolysin (CDC), pneumolysin. Although pneumolysin-induced inflammation drives person-to-person transmission from nasopharynx, the primary reservoir for pneumococcus, it also contributes to high mortality rates, creating a bottleneck that hampers widespread bacterial dissemination, thus acting as a double-edged sword. Serotype 1 ST306, a widespread pneumococcal clone, harbours a non-hemolytic variant of pneumolysin (Ply-NH). Performing crystal structure analysis of Ply-NH, we identified Y150H and T172I as key substitutions responsible for loss of its pore forming activity. We uncovered a novel inter-molecular cation-π interaction, governing formation of the transmembrane β-hairpins (TMH) in the pore state of Ply, which can be extended to other CDCs. H150 in Ply-NH disrupts this interaction, while I172 provides structural rigidity to domain-3, through hydrophobic interactions, inhibiting TMH formation. Loss of pore forming activity enabled improved cellular invasion and autophagy evasion, promoting an atypical intracellular lifestyle for pneumococcus, a finding that was corroborated in in vivo infection models. Attenuation of inflammatory responses and tissue damage promoted tolerance of Ply-NH-expressing pneumococcus in the lower respiratory tract. Adoption of this altered lifestyle may be necessary for ST306 due to its limited nasopharyngeal carriage, with Ply-NH, aided partly by loss of its pore forming ability, facilitating a benign association of SPN in an alternative, intracellular host niche.
Identifiants
pubmed: 33216805
doi: 10.1371/journal.ppat.1009016
pii: PPATHOGENS-D-20-01305
pmc: PMC7717573
doi:
Substances chimiques
Bacterial Proteins
0
Streptolysins
0
plY protein, Streptococcus pneumoniae
0
Perforin
126465-35-8
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009016Subventions
Organisme : Wellcome Trust
ID : 204457/Z/16/Z
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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