Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways

ABSTRACT The purpose of this study was to take advantage of the nematode Caenorhabditis elegans to perform a whole-animal chemical screen to identify potential immune activators that may confer protection against bacterial infections. We identified 45 marketed drugs, out of 1,120 studied compounds,...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yun Cai, Xiou Cao, Alejandro Aballay
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/31babc68d8fb49bea5192fb7c09f0245
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:31babc68d8fb49bea5192fb7c09f0245
record_format	dspace
spelling	oai:doaj.org-article:31babc68d8fb49bea5192fb7c09f02452021-11-15T15:47:22ZWhole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways10.1128/mBio.01235-142150-7511https://doaj.org/article/31babc68d8fb49bea5192fb7c09f02452014-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01235-14https://doaj.org/toc/2150-7511ABSTRACT The purpose of this study was to take advantage of the nematode Caenorhabditis elegans to perform a whole-animal chemical screen to identify potential immune activators that may confer protection against bacterial infections. We identified 45 marketed drugs, out of 1,120 studied compounds, that are capable of activating a conserved p38/PMK-1 mitogen-activated protein kinase pathway required for innate immunity. One of these drugs, the last-resort antibiotic colistin, protected against infections by the Gram-negative pathogens Yersinia pestis and Pseudomonas aeruginosa but not by the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Protection was independent of the antibacterial activity of colistin, since the drug was administered prophylactically prior to the infections and it was also effective against antibiotic-resistant bacteria. Immune activation by colistin is mediated not only by the p38/PMK-1 pathway but also by the conserved FOXO transcription factor DAF-16 and the transcription factor SKN-1. Furthermore, p38/PMK-1 was found to be required in the intestine for immune activation by colistin. Enhanced p38/PMK-1-mediated immune responses by colistin did not reduce the bacterial burden, indicating that the pathway plays a role in the development of host tolerance to infections by Gram-negative bacteria. IMPORTANCE The innate immune system represents the front line of our defenses against invading microorganisms. Given the ever-increasing resistance to antibiotics developed by bacterial pathogens, the possibility of boosting immune defenses represents an interesting, complementary approach to conventional antibiotic treatments. Here we report that the antibiotic colistin can protect against infections by a mechanism that is independent of its microbicidal activity. Prophylactic treatment with colistin activates a conserved p38/PMK-1 pathway in the intestine that helps the host better tolerate a bacterial infection. Since p38/PMK-1-mediated immune responses appear to be conserved from plants to mammals, colistin may also activate immunity in higher organisms, including humans. Antibiotics with immunomodulatory properties have the potential of improving the long-term outcome of patients with chronic infectious diseases.Yun CaiXiou CaoAlejandro AballayAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 4 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Yun Cai Xiou Cao Alejandro Aballay Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways
description	ABSTRACT The purpose of this study was to take advantage of the nematode Caenorhabditis elegans to perform a whole-animal chemical screen to identify potential immune activators that may confer protection against bacterial infections. We identified 45 marketed drugs, out of 1,120 studied compounds, that are capable of activating a conserved p38/PMK-1 mitogen-activated protein kinase pathway required for innate immunity. One of these drugs, the last-resort antibiotic colistin, protected against infections by the Gram-negative pathogens Yersinia pestis and Pseudomonas aeruginosa but not by the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Protection was independent of the antibacterial activity of colistin, since the drug was administered prophylactically prior to the infections and it was also effective against antibiotic-resistant bacteria. Immune activation by colistin is mediated not only by the p38/PMK-1 pathway but also by the conserved FOXO transcription factor DAF-16 and the transcription factor SKN-1. Furthermore, p38/PMK-1 was found to be required in the intestine for immune activation by colistin. Enhanced p38/PMK-1-mediated immune responses by colistin did not reduce the bacterial burden, indicating that the pathway plays a role in the development of host tolerance to infections by Gram-negative bacteria. IMPORTANCE The innate immune system represents the front line of our defenses against invading microorganisms. Given the ever-increasing resistance to antibiotics developed by bacterial pathogens, the possibility of boosting immune defenses represents an interesting, complementary approach to conventional antibiotic treatments. Here we report that the antibiotic colistin can protect against infections by a mechanism that is independent of its microbicidal activity. Prophylactic treatment with colistin activates a conserved p38/PMK-1 pathway in the intestine that helps the host better tolerate a bacterial infection. Since p38/PMK-1-mediated immune responses appear to be conserved from plants to mammals, colistin may also activate immunity in higher organisms, including humans. Antibiotics with immunomodulatory properties have the potential of improving the long-term outcome of patients with chronic infectious diseases.
format	article
author	Yun Cai Xiou Cao Alejandro Aballay
author_facet	Yun Cai Xiou Cao Alejandro Aballay
author_sort	Yun Cai
title	Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways
title_short	Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways
title_full	Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways
title_fullStr	Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways
title_full_unstemmed	Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways
title_sort	whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/31babc68d8fb49bea5192fb7c09f0245
work_keys_str_mv	AT yuncai wholeanimalchemicalscreenidentifiescolistinasanewimmunomodulatorthattargetsconservedpathways AT xioucao wholeanimalchemicalscreenidentifiescolistinasanewimmunomodulatorthattargetsconservedpathways AT alejandroaballay wholeanimalchemicalscreenidentifiescolistinasanewimmunomodulatorthattargetsconservedpathways
_version_	1718427508298219520

Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways

Ejemplares similares