The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia

ABSTRACT Pseudomonas aeruginosa is a Gram-negative pathogen commonly associated with nosocomial infections such as hospital-acquired pneumonia. It uses a type III secretion system to deliver effector proteins directly into the cytosol of host cells. Type III secretion in P. aeruginosa has been linke...

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Autores principales:	Stephanie M. Rangel, Latania K. Logan, Alan R. Hauser
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/18973401cf3a4704be3b1eaf0611cf1c
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spelling	oai:doaj.org-article:18973401cf3a4704be3b1eaf0611cf1c2021-11-15T15:47:38ZThe ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia10.1128/mBio.01080-142150-7511https://doaj.org/article/18973401cf3a4704be3b1eaf0611cf1c2014-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01080-14https://doaj.org/toc/2150-7511ABSTRACT Pseudomonas aeruginosa is a Gram-negative pathogen commonly associated with nosocomial infections such as hospital-acquired pneumonia. It uses a type III secretion system to deliver effector proteins directly into the cytosol of host cells. Type III secretion in P. aeruginosa has been linked to severe disease and worse clinical outcomes in animal and human studies. The majority of P. aeruginosa strains secrete ExoS, a bifunctional toxin with GTPase-activating protein and ADP-ribosyltransferase activities. Numerous in vitro studies have investigated the targets and cellular effects of ExoS, linking both its enzymatic activities with inhibition of bacterial internalization. However, little is known about how this toxin facilitates the progression of infection in vivo. In this study, we used a mouse model to investigate the role of ExoS in inhibiting phagocytosis during pneumonia. We first confirmed previous findings that the ADP-ribosyltransferase activity of ExoS, but not the GTPase-activating protein activity, was responsible for bacterial persistence and decreased host survival in this model. We then used two distinct assays to demonstrate that ExoS inhibited phagocytosis during pneumonia. In contrast to the findings of several in vitro studies, this in vivo inhibition was also dependent on the ADP-ribosyltransferase activity, but not the GTPase-activating protein activity, of ExoS. These results demonstrate for the first time the antiphagocytic function of ExoS in the context of an actual infection and indicate that blocking the ADP-ribosyltransferase activity of ExoS may have potential therapeutic benefit. IMPORTANCE Pseudomonas aeruginosa is a major cause of hospital-acquired infections. To cause severe disease, this bacterium uses a type III secretion system that delivers four effector proteins, ExoS, ExoT, ExoU, and ExoY, into host cells. The majority of P. aeruginosa strains secrete ExoS, a bifunctional toxin with GTPase-activating protein and ADP-ribosyltransferase activities. In cell culture models, both enzymatic activities have been associated with decreased bacterial internalization. However, our study is the first to examine a role for ExoS in blocking phagocytosis in an animal model. We report that ExoS does inhibit phagocytosis during pneumonia. The ADP-ribosyltransferase activity, but not the GTPase-activating protein activity, of ExoS is necessary for this effect. Our findings highlight the ability of P. aeruginosa to manipulate the inflammatory response during pneumonia to facilitate bacterial survival.Stephanie M. RangelLatania K. LoganAlan R. HauserAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 3 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Stephanie M. Rangel Latania K. Logan Alan R. Hauser The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia
description	ABSTRACT Pseudomonas aeruginosa is a Gram-negative pathogen commonly associated with nosocomial infections such as hospital-acquired pneumonia. It uses a type III secretion system to deliver effector proteins directly into the cytosol of host cells. Type III secretion in P. aeruginosa has been linked to severe disease and worse clinical outcomes in animal and human studies. The majority of P. aeruginosa strains secrete ExoS, a bifunctional toxin with GTPase-activating protein and ADP-ribosyltransferase activities. Numerous in vitro studies have investigated the targets and cellular effects of ExoS, linking both its enzymatic activities with inhibition of bacterial internalization. However, little is known about how this toxin facilitates the progression of infection in vivo. In this study, we used a mouse model to investigate the role of ExoS in inhibiting phagocytosis during pneumonia. We first confirmed previous findings that the ADP-ribosyltransferase activity of ExoS, but not the GTPase-activating protein activity, was responsible for bacterial persistence and decreased host survival in this model. We then used two distinct assays to demonstrate that ExoS inhibited phagocytosis during pneumonia. In contrast to the findings of several in vitro studies, this in vivo inhibition was also dependent on the ADP-ribosyltransferase activity, but not the GTPase-activating protein activity, of ExoS. These results demonstrate for the first time the antiphagocytic function of ExoS in the context of an actual infection and indicate that blocking the ADP-ribosyltransferase activity of ExoS may have potential therapeutic benefit. IMPORTANCE Pseudomonas aeruginosa is a major cause of hospital-acquired infections. To cause severe disease, this bacterium uses a type III secretion system that delivers four effector proteins, ExoS, ExoT, ExoU, and ExoY, into host cells. The majority of P. aeruginosa strains secrete ExoS, a bifunctional toxin with GTPase-activating protein and ADP-ribosyltransferase activities. In cell culture models, both enzymatic activities have been associated with decreased bacterial internalization. However, our study is the first to examine a role for ExoS in blocking phagocytosis in an animal model. We report that ExoS does inhibit phagocytosis during pneumonia. The ADP-ribosyltransferase activity, but not the GTPase-activating protein activity, of ExoS is necessary for this effect. Our findings highlight the ability of P. aeruginosa to manipulate the inflammatory response during pneumonia to facilitate bacterial survival.
format	article
author	Stephanie M. Rangel Latania K. Logan Alan R. Hauser
author_facet	Stephanie M. Rangel Latania K. Logan Alan R. Hauser
author_sort	Stephanie M. Rangel
title	The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia
title_short	The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia
title_full	The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia
title_fullStr	The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia
title_full_unstemmed	The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia
title_sort	adp-ribosyltransferase domain of the effector protein exos inhibits phagocytosis of <named-content content-type="genus-species">pseudomonas aeruginosa</named-content> during pneumonia
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/18973401cf3a4704be3b1eaf0611cf1c
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The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content> during Pneumonia

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