Pseudomonas aeruginosa Suppresses Host Immunity by Activating the DAF-2 Insulin-Like Signaling Pathway in Caenorhabditis elegans

Authors:
Open Access
Publisher website
Google Scholar
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. Bacterial pathogens have evolved mechanisms to overcome the immune defenses that animals and plants deploy against them. In some cases, this involves directly interfering with the proper functioning of the immune system. Because pathogens that employ these strategies are often the most deadly and difficult to treat, it is important to understand how they are able to suppress the immune system in the context of the whole organism. In this paper, we show that Pseudomonas aeruginosa, a bacterial pathogen that is a major contributor to hospital-borne infections such as pneumonia, suppresses an immune defense pathway during infection of the simple animal host Caenorhabditis elegans. Using genetic modifications of both the pathogen and host, we identify components of the signaling pathways required to suppress host immune defenses. 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. In the host, an evolutionarily conserved insulin-like signaling pathway is affected by P. aeruginosa, resulting in the suppression of genes that are required for defense against infection in the intestinal epithelial cells. These findings suggest the possibility that P. aeruginosa may exploit similar mechanisms when causing infections of human epithelium, such as the epithelial lining of the lungs.

This publication has 100 references indexed in Scilit: