Abstract

Some pathogens have evolved mechanisms to overcome host immune defenses by inhibiting host defense signaling pathways and suppressing the expression of host defense effectors. We present evidence that Pseudomonas aeruginosa is able to suppress the expression of a subset of immune defense genes in the animal host Caenorhabditis elegans by activating the DAF-2/DAF-16 insulin-like signaling pathway. The DAF-2/DAF-16 pathway is important for the regulation of many aspects of organismal physiology, including metabolism, stress response, longevity, and immune function. We show that intestinal expression of DAF-16 is required for resistance to P. aeruginosa and that the suppression of immune defense genes is dependent on the insulin-like receptor DAF-2 and the FOXO transcription factor DAF-16. By visualizing the subcellular localization of DAF-16::GFP fusion protein in live animals during infection, we show that P. aeruginosa–mediated downregulation of a subset of immune genes is associated with the ability to translocate DAF-16 from the nuclei of intestinal cells. Suppression of DAF-16 is mediated by an insulin-like peptide, INS-7, which functions upstream of DAF-2. Both the inhibition of DAF-16 and downregulation of DAF-16–regulated genes, such as thn-2, lys-7, and spp-1, require the P. aeruginosa two-component response regulator GacA and the quorum-sensing regulators LasR and RhlR and are not observed during infection with Salmonella typhimurium or Enterococcus faecalis. Our results reveal a new mechanism by which P. aeruginosa suppresses host immune defense.

Highlights

  • The innate immune system is a genetically-encoded host defense mechanism that constitutes the first line of defense against pathogens in plants and animals

  • We show that Pseudomonas aeruginosa, a bacterial pathogen that is a major contributor to hospitalborne infections such as pneumonia, suppresses an immune defense pathway during infection of the simple animal host Caenorhabditis elegans

  • We find that P. aeruginosa employs the cell-to-cell communication system known as quorum sensing, which coordinates the expression of virulence factors to suppress host immune defense

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Summary

Introduction

The innate immune system is a genetically-encoded host defense mechanism that constitutes the first line of defense against pathogens in plants and animals. Despite lacking a functionally conserved TLR/NF-kB pathway [6], C. elegans is able to mount robust immune responses against a variety of pathogens (see [7,8,9,10] for examples). This underscores the importance of other pathways in C. elegans innate immunity. Through genetic studies, several conserved signal transduction pathways that are required for innate immunity in C. elegans have been identified They include the p38 MAPK, the Sma/TGF-b, and the DAF-2/DAF-16 insulinlike signaling pathways (reviewed in [11,12]). Microarray studies suggest that each of these immune signaling pathways regulates the expression of host effector genes, which may account for the altered pathogen susceptibility of pathway mutants [8,16,17]

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