Imperial College London
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DrThomasClarke

Faculty of Medicine, Department of Infectious Disease

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 2074thomas.clarke

 
 
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Location

 

5.40DFlowers buildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Torraca:2019:10.1371/journal.ppat.1008006,
author = {Torraca, V and Kaforou, M and Watson, J and Duggan, GM and Guerrero-Gutierrez, H and Krokowski, S and Hollinshead, M and Clarke, TB and Mostowy, RJ and Tomlinson, GS and Sancho-Shimizu, V and Clements, A and Mostowy, S},
doi = {10.1371/journal.ppat.1008006},
journal = {PLoS Pathogens},
pages = {1--26},
title = {Shigella sonnei infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence},
url = {http://dx.doi.org/10.1371/journal.ppat.1008006},
volume = {15},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Shigella flexneri is historically regarded as the primary agent of bacillary dysentery, yet the closely-related Shigella sonnei is replacing S. flexneri, especially in developing countries. The underlying reasons for this dramatic shift are mostly unknown. Using a zebrafish (Danio rerio) model of Shigella infection, we discover that S. sonnei is more virulent than S. flexneri in vivo. Whole animal dual-RNAseq and testing of bacterial mutants suggest that S. sonnei virulence depends on its O-antigen oligosaccharide (which is unique among Shigella species). We show in vivo using zebrafish and ex vivo using human neutrophils that S. sonnei O-antigen can mediate neutrophil tolerance. Consistent with this, we demonstrate that O-antigen enables S. sonnei to resist phagolysosome acidification and promotes neutrophil cell death. Chemical inhibition or promotion of phagolysosome maturation respectively decreases and increases neutrophil control of S. sonnei and zebrafish survival. Strikingly, larvae primed with a sublethal dose of S. sonnei are protected against a secondary lethal dose of S. sonnei in an O-antigen-dependent manner, indicating that exposure to O-antigen can train the innate immune system against S. sonnei. Collectively, these findings reveal O-antigen as an important therapeutic target against bacillary dysentery, and may explain the rapidly increasing S. sonnei burden in developing countries.
AU  - Torraca,V
AU  - Kaforou,M
AU  - Watson,J
AU  - Duggan,GM
AU  - Guerrero-Gutierrez,H
AU  - Krokowski,S
AU  - Hollinshead,M
AU  - Clarke,TB
AU  - Mostowy,RJ
AU  - Tomlinson,GS
AU  - Sancho-Shimizu,V
AU  - Clements,A
AU  - Mostowy,S
DO  - 10.1371/journal.ppat.1008006
EP  - 26
PY  - 2019///
SN  - 1553-7366
SP  - 1
TI  - Shigella sonnei infection of zebrafish reveals that O-antigen mediates neutrophil tolerance and dysentery incidence
T2  - PLoS Pathogens
UR  - http://dx.doi.org/10.1371/journal.ppat.1008006
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000507327900055&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008006
UR  - http://hdl.handle.net/10044/1/77071
VL  - 15
ER  -
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