Badgujar, Dilip C, Anil, Anjali, Green, Angharad E ORCID: 0000-0002-8683-8191, Surve, Manalee Vishnu, Madhavan, Shilpa, Beckett, Alison ORCID: 0000-0001-8377-325X, Prior, Ian A ORCID: 0000-0002-4055-5161, Godsora, Barsa K, Patil, Sanket B, More, Prachi Kadam et al (show 8 more authors)
(2020)
Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellular lifestyle.
PLOS PATHOGENS, 16 (11).
e1009016-.
Text
Structural insights into loss of function of a pore forming toxin and its role in pneumococcal adaptation to an intracellula.pdf - Published version Download (4MB) | Preview |
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. 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.
Item Type: | Article |
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Uncontrolled Keywords: | Cell Membrane, Cytoplasm, Animals, Humans, Mice, Streptococcus pneumoniae, Pneumococcal Infections, Inflammation, Cholesterol, Bacterial Proteins, Streptolysins, Sequence Alignment, Adaptation, Physiological, Amino Acid Sequence, Models, Structural, Female, Perforin, Loss of Function Mutation |
Depositing User: | Symplectic Admin |
Date Deposited: | 15 Jan 2021 09:16 |
Last Modified: | 18 Jan 2023 23:03 |
DOI: | 10.1371/journal.ppat.1009016 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3113648 |