OVERALL PROJECT SUMMARY This renewal application requests the continued funding of our Genomics Center for Infectious Disease (GCID) in the Texas Medical Center (TMC) which comprises a multidisciplinary, integrated team of basic and physician scientists at Baylor College of Medicine, the University of Texas-Houston School of Public Health, MD Anderson Cancer Center, and Rice University. The TMC-GCID: i) leverages our decades of experience in genomic sequencing technology with our renowned clinical expertise, and the use of novel ex vivo organotypic models of human intestinal and pulmonary function, to create a platform for large scale genomics-based interrogation of host-mucosal pathogen interactions in the context of human tissues, and ii) utilizes this platform for the discovery of novel therapeutic and diagnostic targets based on host and microbial genomic and transcriptomic profiles. Project 1 (PL: A. Maresso, PhD) will build on discoveries made from dissecting genomic elements of pathogenic members of the Enterobacteriaceae that associate with human intestinal mucosa colonization and translocation. Project 2 (PL: R. Atmar, MD, S. Ramani, PhD and T. Piedra, MD, PhD) will continue integrated analyses of human norovirus and respiratory syncytial virus full-length genomic sequences and characterization of the ecological niche of samples from clinically relevant patient sub-groups for new understanding of viral replication, recombination and evolution, induction of disease and host factors required for susceptibility to infection and pathogenesis. Project 3 (PL: M. Lorenz, PhD) will examine the impact of commensal Candida albicans on gut health and susceptibility to disease. Surprisingly little is known about the genetic diversity of C. albicans isolated from the gut (as compared to those isolated from the skin, for example). Mapping the fungal-host-microbiome interplay in relevant gut niches using the latest genomic, metagenomic and metatranscriptomic technologies will greatly improve the understanding of how commensal fungi can influence gut homeostasis. Project 4 (PL: P. Okhuysen, MD) will build on a novel Cryptosporidium discovery made by the project leaders and test the hypothesis that one or more indole-producing commensal microbes in the gut can prevent or eliminate Cryptosporidium infection. All four research projects will continue to utilize human intestinal and lung organoid cultures along with niche-specific, defined microbial communities supplied by the Organoid and Minibioreactor Array Cultivation Core. Meanwhile cutting edge, high-throughput sequencing strategies and technologies and the latest analysis tools and outputs will be supplied, and disseminated, by the Sequencing Analysis and Resource Dissemination (SARD) Core. The result will be a comprehensive genetic profiling of hosts and microbes in human infection models that will reveal pathogen genetic variants, and individual host response phenotypes to inform precision medicine-...