Host stress and virulence expression in intestinal pathogens: development of therapeutic strategies using mice and C. elegans

Abstract

The intestinal tract of a host exposed to extreme physiologic stress and modern medical intervention represents a relatively unexplored yet important area of infection research, given the frequency with which this site becomes colonized by highly pathogenic microorganisms that cause subsequent sepsis. Our laboratory has focused on the host tissue derived environmental cues that are released into the intestinal tract during extreme physiologic stress that induce the expression of virulence in colonizing pathogens with the goal of developing novel gut directed therapies that maintain host pathogen neutrality through the course of host stress. Here we demonstrate that maintenance of phosphate sufficiency/ abundance within the intestinal microenvironment may be considered as a universal strategy to prevent virulence activation across a broad range of pathogens that colonize the gut and cause sepsis, given that phosphate depletion occurs following stress and is a universal cue that activates the virulence of a wide variety of organisms. Using small animal models (Caenorhabditis elegans and mice) to create local phosphate depletion at sites of colonization of Pseudomonas aeruginosa, a common cause of lethal gut-derived sepsis, we demonstrate the importance of maintaining phosphate sufficiency to suppress the expression of a lethal phenotype during extreme physiologic stress. The molecular details and potential therapeutic implications are reviewed.

Fig. 1

The potential role of aggregated disordering agents on the intestinal microbiota that accrue from the effects and treatment modalities of human critical illness.

Fig. 2

Mouse model of a surgical (30%) liver resection (hepatectomy) with simultaneous intestinal exposure to P. aeruginosa that leads to acute phosphate depletion in the distal (ileum, cecum) intestinal mucus layer.

Fig. 3

C. elegans model of phosphate limitation.

Fig. 4

Discovery platform of the C. elegans- P. aeruginosa model. A. Genes are identified from whole genome transcriptional profiling. B. Post translational studies are conducted by measuring secreted compounds directly (MS, fluorescence) or using protein fusion reporter constructs. C. Selected mutants of identified systems are screened for their killing effect on C. elegans. D. Data are then reconstructed, hypotheses developed, and then re-interrogated in the C. elegans model and in mice.

Fig. 5

Artificial lawns containing [PQS-Fe3+-rhamnolipid] complex. A. Creation of artificial lawns. B. Accumulation of the red colored complex inside the intestinal tube of worms (arrow). C. Mortality in worms feeding on artificial lawns.