Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle

PLoS Pathogens
D. C. BadgujarAnirban Banerjee

Abstract

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. Lo...Continue Reading

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Datasets Mentioned

BETA
GM-CSF
AAK75991.1
CAC94851.1
BAA89790.1
ACD39461.1
AQY45513.1
CAA42639.1
CAA42996.1
AAC45754.1
BAV54146.1

Methods Mentioned

BETA
Fluorescence
density gradient centrifugation
Dot blot
bronchoalveolar lavage
lavage
lavages
PCR
ELISA
circular dichroism
X-ray

Software Mentioned

NH
PyMOL
Tree Star
MODEL
- Avizo
FlowJo
Amira
Image J
Clustal W
PHENIX

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