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

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...

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Autores principales: Badgujar, Dilip C., Anil, Anjali, Green, Angharad E., Surve, Manalee Vishnu, Madhavan, Shilpa, Beckett, Alison, Prior, Ian A., Godsora, Barsa K., Patil, Sanket B., More, Prachi Kadam, Sarkar, Shruti Guha, Mitchell, Andrea, Banerjee, Rinti, Phale, Prashant S., Mitchell, Timothy J., Neill, Daniel R., Bhaumik, Prasenjit, Banerjee, Anirban
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717573/
https://www.ncbi.nlm.nih.gov/pubmed/33216805
http://dx.doi.org/10.1371/journal.ppat.1009016
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author Badgujar, Dilip C.
Anil, Anjali
Green, Angharad E.
Surve, Manalee Vishnu
Madhavan, Shilpa
Beckett, Alison
Prior, Ian A.
Godsora, Barsa K.
Patil, Sanket B.
More, Prachi Kadam
Sarkar, Shruti Guha
Mitchell, Andrea
Banerjee, Rinti
Phale, Prashant S.
Mitchell, Timothy J.
Neill, Daniel R.
Bhaumik, Prasenjit
Banerjee, Anirban
author_facet Badgujar, Dilip C.
Anil, Anjali
Green, Angharad E.
Surve, Manalee Vishnu
Madhavan, Shilpa
Beckett, Alison
Prior, Ian A.
Godsora, Barsa K.
Patil, Sanket B.
More, Prachi Kadam
Sarkar, Shruti Guha
Mitchell, Andrea
Banerjee, Rinti
Phale, Prashant S.
Mitchell, Timothy J.
Neill, Daniel R.
Bhaumik, Prasenjit
Banerjee, Anirban
author_sort Badgujar, Dilip C.
collection PubMed
description 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.
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spelling pubmed-77175732020-12-09 Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle Badgujar, Dilip C. Anil, Anjali Green, Angharad E. Surve, Manalee Vishnu Madhavan, Shilpa Beckett, Alison Prior, Ian A. Godsora, Barsa K. Patil, Sanket B. More, Prachi Kadam Sarkar, Shruti Guha Mitchell, Andrea Banerjee, Rinti Phale, Prashant S. Mitchell, Timothy J. Neill, Daniel R. Bhaumik, Prasenjit Banerjee, Anirban PLoS Pathog Research Article 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. Public Library of Science 2020-11-20 /pmc/articles/PMC7717573/ /pubmed/33216805 http://dx.doi.org/10.1371/journal.ppat.1009016 Text en © 2020 Badgujar et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Badgujar, Dilip C.
Anil, Anjali
Green, Angharad E.
Surve, Manalee Vishnu
Madhavan, Shilpa
Beckett, Alison
Prior, Ian A.
Godsora, Barsa K.
Patil, Sanket B.
More, Prachi Kadam
Sarkar, Shruti Guha
Mitchell, Andrea
Banerjee, Rinti
Phale, Prashant S.
Mitchell, Timothy J.
Neill, Daniel R.
Bhaumik, Prasenjit
Banerjee, Anirban
Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle
title Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle
title_full Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle
title_fullStr Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle
title_full_unstemmed Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle
title_short Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle
title_sort structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717573/
https://www.ncbi.nlm.nih.gov/pubmed/33216805
http://dx.doi.org/10.1371/journal.ppat.1009016
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