Interactions of Intestinal Epithelial Cells, The Innate Immune System and Gut Microbiota During Dysbiosis

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PROJECT SUMMARY/ABSTRACT Candidate: The applicant is an instructor in the Allergy and Clinical Immunology Division at the University of Colorado Anschutz Medical Campus. The applicant’s thesis work under the mentorship of Dr. Ramesh Akkina at Colorado State University focused on translational research utilizing humanized mice to develop novel therapies against HIV infection. During his Post-doctoral training, Dr. Neff developed methods to characterize the impact of the fecal microbiome on adaptive immune cells, found regulatory T cell inducing products in bacteria and characterized the impact of HIV infection on immune cells in the lung. Environment: At the University of Colorado, the applicant has a mentoring team with immunology, mucosal immunology, inflammation and microbiome expertise in primary mentor Dr. Brent Palmer, and co-mentors Drs. Catherine Lozupone, Sean Colgan, and Laurel Lenz. The applicant will continue close collaboration with Drs. Nichole Reisdorph and Timothy Bushnell who will serve as technical advisors for UPLC, mass spectrometry and CyTOF. The applicant’s training plan during the award includes bioinformatics, immunology, biostatistics, responsible conduct of research, and programs in grant writing and career development. Research: Chronic immune activation is a hallmark of HIV infection and recently, changes in the composition of the enteric microbiome have been implicated as a driving factor. However, the mechanisms of host:microbiome interactions are poorly understood. We showed that the fecal microbiome from those with HIV has inflammatory properties not seen in taxonomically similar healthy subjects. Using this HIV-associated microbiome as a model present a unique opportunity to identify causal bacteria and the mechanisms in which they lead to cell activation. The applicant’s long-term goal is to develop a deeper understanding of the bacterial products that drive chronic immune activation as a means to advance treatment strategies for inflammatory gastrointestinal diseases. This proposal will evaluate the mechanisms of microbiota:host interactions. Based on previous findings, which indicated peptidoglycan (PGN) and lipopolysaccharide (LPS) as drivers of inflammatory responses, this proposal will also investigate if specific variants of PGN and LPS differentially induce aberrant activation. The central hypothesis is that specific PGN and LPS forms found with bacteria increased during HIV convey differential inflammatory properties. The first aim will characterize the interactions of epithelial cells, subsets of innate immune cells and the microbiome during HIV dysbiosis in order to determine rare bacteria that cause inflammation. The second aim will focus on purifying PGN and LPS to determine if strain specific forms of these bacterial products are responsible for inducing aberrant cell activation. The findings here could have global implications of the treatment of chronic immune activation seen in multiple diseases.