Lipid-dependent host-microbe interactions

PROJECT SUMMARY Lipids serve as important mediators of host-microbe interactions yet many mechanisms that support signaling through these interactions have yet to be characterized. Of special interest are classes of lipids that have well- defined signaling pathways in host systems but have less well understood synthesis pathways in microbial systems. My research program has focused on defining how a class of lipids, the sphingolipids, can mediate interkingdom host-microbe interactions through the functions of these lipids as structural components of membranes and as chemical signals. To understand the importance of sphingolipids to host-microbe interactions, we have developed techniques to trace sphingolipid transfer through these interactions. These efforts have alerted to us to under characterized pathways in microbial sphingolipid metabolism that we have been able to profile and manipulate to deepen our understanding of the importance of microbial sphingolipid metabolism to host-microbe interactions. We have integrated techniques in microbial genetics, biochemistry, flow cytometry, high-throughput sequencing, and liquid chromatography-mass spectrometry to define host- microbe sphingolipid transfer and characterize key microbial sphingolipid metabolism genes. Our innovations in investigating sphingolipid-dependent host-microbe systems have the potential to accelerate discovery in a range of host-microbe systems and for a wide range of metabolites. To capitalize on this potential, we have used our workflows to investigate new ways that cholesterol mediates host-microbe interactions and propose to expand to other classes of bioactive lipids. The goals for the next five years of the research program are to use techniques developed from our investigations into sphingolipid-dependent host-microbe interactions to accelerate knowledge of how the important lipid classes of sphingolipids, cholesterol, and fatty acids mediate host-microbe interactions. For sphingolipid-dependent host-microbe interactions, we plan to further define genes contributing to bacterial sphingolipid metabolism and determine how this gene activity may generate bioactive signaling molecules with relevance to prominent host cellular receptors. For cholesterol-dependent host-microbe interactions, we plan to further define microbial metabolites produced from exogenous cholesterol and expand on investigations into how microbial cholesterol sulfotransferase activity regulates microbial and host phenotypes. For fatty-acid dependent microbe interactions, we plan to define the microbes that interact with distinct saturated and unsaturated fatty acids as well as the potential suite of bioactive metabolites produced from these interactions. Together, these efforts will deepen our knowledge on how lipids mediate host-microbe interactions at a level that can inform microbiome-centric therapeutic interventions.