Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection

Abstract Group A Streptoccocus (GAS) is among the most diverse of all human pathogens, responsible for a range of clinical manifestations, from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different dise...

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Autores principales:	Jenny Clarke, Murielle Baltazar, Mansoor Alsahag, Stavros Panagiotou, Marion Pouget, William A. Paxton, Georgios Pollakis, Dean Everett, Neil French, Aras Kadioglu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e82387792e7e4a6985178eb539edf824
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spelling	oai:doaj.org-article:e82387792e7e4a6985178eb539edf8242021-12-02T17:27:02ZStreptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection10.1038/s41598-021-97866-42045-2322https://doaj.org/article/e82387792e7e4a6985178eb539edf8242021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97866-4https://doaj.org/toc/2045-2322Abstract Group A Streptoccocus (GAS) is among the most diverse of all human pathogens, responsible for a range of clinical manifestations, from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different disease phenotypes are not known. The GAS cholesterol-dependent cytolysin, Streptolysin O (SLO), has well established cell and tissue destructive activity. We investigated the role of SLO in determining disease outcome in vivo, by using two different clinical lineages; the recently emerged hypervirulent outbreak emm type 32.2 strains, which result in sepsis, and the emm type 1.0 strains which cause septic arthritis. Using clinically relevant in vivo mouse models of sepsis and a novel septic arthritis model, we found that the amount and activity of SLO was vital in determining the course of infection. The emm type 32.2 strain produced large quantities of highly haemolytic SLO that resulted in rapid development of sepsis. By contrast, the reduced concentration and lower haemolytic activity of emm type 1.0 SLO led to translocation of bacteria from blood to joints. Importantly, sepsis associated strains that were attenuated by deletion or inhibition of SLO, then also translocated to the joint, confirming the key role of SLO in determining infection niche. Our findings demonstrate that SLO is key to in vivo phenotype and disease outcome. Careful consideration should be given to novel therapy or vaccination strategies that target SLO. Whilst neutralising SLO activity may reduce severe invasive disease, it has the potential to promote chronic inflammatory conditions such as septic arthritis.Jenny ClarkeMurielle BaltazarMansoor AlsahagStavros PanagiotouMarion PougetWilliam A. PaxtonGeorgios PollakisDean EverettNeil FrenchAras KadiogluNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jenny Clarke Murielle Baltazar Mansoor Alsahag Stavros Panagiotou Marion Pouget William A. Paxton Georgios Pollakis Dean Everett Neil French Aras Kadioglu Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection
description	Abstract Group A Streptoccocus (GAS) is among the most diverse of all human pathogens, responsible for a range of clinical manifestations, from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different disease phenotypes are not known. The GAS cholesterol-dependent cytolysin, Streptolysin O (SLO), has well established cell and tissue destructive activity. We investigated the role of SLO in determining disease outcome in vivo, by using two different clinical lineages; the recently emerged hypervirulent outbreak emm type 32.2 strains, which result in sepsis, and the emm type 1.0 strains which cause septic arthritis. Using clinically relevant in vivo mouse models of sepsis and a novel septic arthritis model, we found that the amount and activity of SLO was vital in determining the course of infection. The emm type 32.2 strain produced large quantities of highly haemolytic SLO that resulted in rapid development of sepsis. By contrast, the reduced concentration and lower haemolytic activity of emm type 1.0 SLO led to translocation of bacteria from blood to joints. Importantly, sepsis associated strains that were attenuated by deletion or inhibition of SLO, then also translocated to the joint, confirming the key role of SLO in determining infection niche. Our findings demonstrate that SLO is key to in vivo phenotype and disease outcome. Careful consideration should be given to novel therapy or vaccination strategies that target SLO. Whilst neutralising SLO activity may reduce severe invasive disease, it has the potential to promote chronic inflammatory conditions such as septic arthritis.
format	article
author	Jenny Clarke Murielle Baltazar Mansoor Alsahag Stavros Panagiotou Marion Pouget William A. Paxton Georgios Pollakis Dean Everett Neil French Aras Kadioglu
author_facet	Jenny Clarke Murielle Baltazar Mansoor Alsahag Stavros Panagiotou Marion Pouget William A. Paxton Georgios Pollakis Dean Everett Neil French Aras Kadioglu
author_sort	Jenny Clarke
title	Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection
title_short	Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection
title_full	Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection
title_fullStr	Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection
title_full_unstemmed	Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection
title_sort	streptolysin o concentration and activity is central to in vivo phenotype and disease outcome in group a streptococcus infection
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e82387792e7e4a6985178eb539edf824
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Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection

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