Whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways

Yun Cai, Xiou Cao, Alejandro Aballay

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 longterm outcome of patients with chronic infectious diseases.

Original languageEnglish (US)
JournalmBio
Volume5
Issue number4
DOIs
StatePublished - Aug 12 2014
Externally publishedYes

Fingerprint

Colistin
Immunologic Factors
Anti-Bacterial Agents
Infection
Bacterial Infections
Intestines
Transcription Factors
Pharmaceutical Preparations
Yersinia pestis
Enterococcus faecalis
Caenorhabditis elegans
Microbial Drug Resistance
Mitogen-Activated Protein Kinases
Gram-Negative Bacteria
Innate Immunity
Pseudomonas aeruginosa
Communicable Diseases
Staphylococcus aureus
Mammals
Immune System

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways. / Cai, Yun; Cao, Xiou; Aballay, Alejandro.

In: mBio, Vol. 5, No. 4, 12.08.2014.

Research output: Contribution to journalArticle

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