The Role of ExoS in Dissemination of Pseudomonas aeruginosa during Pneumonia.
Hospital-acquired pneumonia is associated with high rates of morbidity and mortality, and dissemination to the bloodstream is a recognized risk factor for particularly poor outcomes. Yet the mechanism by which bacteria in the lungs gain access to the bloodstream remains poorly understood. In this st...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-06-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC4474835?pdf=render |
| _version_ | 1818018948057137152 |
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| author | Stephanie M Rangel Maureen H Diaz Claire A Knoten Angelica Zhang Alan R Hauser |
| author_facet | Stephanie M Rangel Maureen H Diaz Claire A Knoten Angelica Zhang Alan R Hauser |
| author_sort | Stephanie M Rangel |
| collection | DOAJ |
| description | Hospital-acquired pneumonia is associated with high rates of morbidity and mortality, and dissemination to the bloodstream is a recognized risk factor for particularly poor outcomes. Yet the mechanism by which bacteria in the lungs gain access to the bloodstream remains poorly understood. In this study, we used a mouse model of Pseudomonas aeruginosa pneumonia to examine this mechanism. P. aeruginosa uses a type III secretion system to deliver effector proteins such as ExoS directly into the cytosol of eukaryotic cells. ExoS, a bi-functional GTPase activating protein (GAP) and ADP-ribosyltransferase (ADPRT), inhibits phagocytosis during pneumonia but has also been linked to a higher incidence of dissemination to the bloodstream. We used a novel imaging methodology to identify ExoS intoxicated cells during pneumonia and found that ExoS is injected into not only leukocytes but also epithelial cells. Phagocytic cells, primarily neutrophils, were targeted for injection with ExoS early during infection, but type I pneumocytes became increasingly injected at later time points. Interestingly, injection of these pneumocytes did not occur randomly but rather in discrete regions, which we designate ""fields of cell injection" (FOCI). These FOCI increased in size as the infection progressed and contained dead type I pneumocytes. Both of these phenotypes were attenuated in infections caused by bacteria secreting ADPRT-deficient ExoS, indicating that FOCI growth and type I pneumocyte death were dependent on the ADPRT activity of ExoS. During the course of infection, increased FOCI size was associated with enhanced disruption of the pulmonary-vascular barrier and increased bacterial dissemination into the blood, both of which were also dependent on the ADPRT activity of ExoS. We conclude that the ADPRT activity of ExoS acts upon type I pneumocytes to disrupt the pulmonary-vascular barrier during P. aeruginosa pneumonia, leading to bacterial dissemination. |
| first_indexed | 2024-04-14T07:46:25Z |
| format | Article |
| id | doaj.art-b6d447c8d59940e69b534b64b382230b |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-14T07:46:25Z |
| publishDate | 2015-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-b6d447c8d59940e69b534b64b382230b2022-12-22T02:05:20ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-06-01116e100494510.1371/journal.ppat.1004945The Role of ExoS in Dissemination of Pseudomonas aeruginosa during Pneumonia.Stephanie M RangelMaureen H DiazClaire A KnotenAngelica ZhangAlan R HauserHospital-acquired pneumonia is associated with high rates of morbidity and mortality, and dissemination to the bloodstream is a recognized risk factor for particularly poor outcomes. Yet the mechanism by which bacteria in the lungs gain access to the bloodstream remains poorly understood. In this study, we used a mouse model of Pseudomonas aeruginosa pneumonia to examine this mechanism. P. aeruginosa uses a type III secretion system to deliver effector proteins such as ExoS directly into the cytosol of eukaryotic cells. ExoS, a bi-functional GTPase activating protein (GAP) and ADP-ribosyltransferase (ADPRT), inhibits phagocytosis during pneumonia but has also been linked to a higher incidence of dissemination to the bloodstream. We used a novel imaging methodology to identify ExoS intoxicated cells during pneumonia and found that ExoS is injected into not only leukocytes but also epithelial cells. Phagocytic cells, primarily neutrophils, were targeted for injection with ExoS early during infection, but type I pneumocytes became increasingly injected at later time points. Interestingly, injection of these pneumocytes did not occur randomly but rather in discrete regions, which we designate ""fields of cell injection" (FOCI). These FOCI increased in size as the infection progressed and contained dead type I pneumocytes. Both of these phenotypes were attenuated in infections caused by bacteria secreting ADPRT-deficient ExoS, indicating that FOCI growth and type I pneumocyte death were dependent on the ADPRT activity of ExoS. During the course of infection, increased FOCI size was associated with enhanced disruption of the pulmonary-vascular barrier and increased bacterial dissemination into the blood, both of which were also dependent on the ADPRT activity of ExoS. We conclude that the ADPRT activity of ExoS acts upon type I pneumocytes to disrupt the pulmonary-vascular barrier during P. aeruginosa pneumonia, leading to bacterial dissemination.http://europepmc.org/articles/PMC4474835?pdf=render |
| spellingShingle | Stephanie M Rangel Maureen H Diaz Claire A Knoten Angelica Zhang Alan R Hauser The Role of ExoS in Dissemination of Pseudomonas aeruginosa during Pneumonia. PLoS Pathogens |
| title | The Role of ExoS in Dissemination of Pseudomonas aeruginosa during Pneumonia. |
| title_full | The Role of ExoS in Dissemination of Pseudomonas aeruginosa during Pneumonia. |
| title_fullStr | The Role of ExoS in Dissemination of Pseudomonas aeruginosa during Pneumonia. |
| title_full_unstemmed | The Role of ExoS in Dissemination of Pseudomonas aeruginosa during Pneumonia. |
| title_short | The Role of ExoS in Dissemination of Pseudomonas aeruginosa during Pneumonia. |
| title_sort | role of exos in dissemination of pseudomonas aeruginosa during pneumonia |
| url | http://europepmc.org/articles/PMC4474835?pdf=render |
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