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Tytuł:
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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.
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Autorzy:
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Badgujar DC; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Anil A; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Green AE; Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom.
Surve MV; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Madhavan S; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Beckett A; Division of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Prior IA; Division of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
Godsora BK; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Patil SB; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
More PK; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Sarkar SG; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Mitchell A; Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Banerjee R; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Phale PS; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Mitchell TJ; Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Neill DR; Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom.
Bhaumik P; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
Banerjee A; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
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Źródło:
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PLoS pathogens [PLoS Pathog] 2020 Nov 20; Vol. 16 (11), pp. e1009016. Date of Electronic Publication: 2020 Nov 20 (Print Publication: 2020).
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: San Francisco, CA : Public Library of Science, c2005-
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MeSH Terms:
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Adaptation, Physiological*
Loss of Function Mutation*
Inflammation/*microbiology
Pneumococcal Infections/*microbiology
Streptococcus pneumoniae/*physiology
Streptolysins/*metabolism
Amino Acid Sequence ; Animals ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Cell Membrane/microbiology ; Cholesterol/metabolism ; Cytoplasm/microbiology ; Female ; Humans ; Mice ; Models, Structural ; Perforin/genetics ; Perforin/metabolism ; Sequence Alignment ; Streptococcus pneumoniae/genetics ; Streptolysins/genetics
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Grant Information:
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204457/Z/16/Z United Kingdom WT_ Wellcome Trust
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Substance Nomenclature:
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0 (Bacterial Proteins)
0 (Streptolysins)
0 (plY protein, Streptococcus pneumoniae)
126465-35-8 (Perforin)
97C5T2UQ7J (Cholesterol)
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Entry Date(s):
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Date Created: 20201120 Date Completed: 20210208 Latest Revision: 20210208
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Update Code:
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20240105
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PubMed Central ID:
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PMC7717573
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DOI:
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10.1371/journal.ppat.1009016
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PMID:
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33216805
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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.
Competing Interests: The authors have declared that no competing interests exist.
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