Detection of pathogen infection by monitoring host cell membrane dynamics

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PROJECT SUMMARY Innate recognition of pathogenic bacteria involves sensing both the physical presence of potentially harmful microbes and the perturbations of host physiology that accompany infection. By monitoring for the effects of pathogen infection on the host rather than for the infectious microorganism itself, surveillance immunity enables the host to direct immune defenses towards bona fide pathogens during an infection and not harmless commensal bacteria. The concept of surveillance immunity was first described in plants and in the nematode C. elegans, and subsequently, a few specific examples have been characterized in mammals. However, it is unknown how pathogen-induced changes in host physiology activate immune defenses. Here, we advance a new hypothesis of innate immune sensing that stems from the concept of surveillance immunity. The central hypothesis of this proposal is that pathogen infection causes a change in the fluidity of intestinal plasma membranes, which is sensed by the host to induce innate immune defenses. Specifically, we propose that pathogen infection alters fatty acid desaturation in the phospholipid compartment of plasma membranes, which reduces their fluidity and leads to activation of intracellular immune signaling cascades. Through genetic studies of host-pathogen interactions in the nematode C. elegans, we made several observations that provide the rationale for this idea: (i) Membrane fluidity dynamics are monitored to activate innate immune defenses. Disruption of a transcriptional regulator of fatty acid biogenesis and desaturation decreases membrane fluidity and causes immune activation in a manner that recapitulates intestinal infection by bacterial pathogens. (ii) The p38 PMK-1 innate immune pathway, a host defense pathway of nematodes, is activated in C. elegans mutants that have membrane fluidity pathology. (iii) Pathogen infection rapidly depletes host fatty acids and suppresses the transcription of genes that synthesize monounsaturated fatty acids. Importantly, we found that pathogen infection also disrupts the fluidity of intestinal epithelial cell plasma membranes. (iv) Finally, cell membrane fluidity is required for pathogen resistance. C. elegans mutants with defects in membrane fluidity are hypersusceptible to pathogen infection, and restoration of membrane fluidity dynamics complements this mutant phenotype. In this proposal, we will characterize host surveillance of intestinal cell plasma membrane fluidity as a novel mechanism to activate innate immunity (Aim 1). We will also define the pathogen-induced changes in membrane composition that decrease plasma membrane fluidity (Aim 2) and determine the mechanism of p38 PMK-1 pathway activation during bacterial infection (Aim 3). The proposed study will define a general strategy employed by C. elegans to detect pathogen-induced disturbances in host physiology, revealing fundamental insights into a previously unrecognized, evolutionarily ancient strategy of immune activation.