This application requests funding for a Genomics Center for Infectious Disease (GCID) in the Texas Medical Center (TMC) that comprises a multidisciplinary, integrated team of basic and physician scientists at Baylor College of Medicine, the University of Texas-Houston School of Public Health, and MD Anderson Cancer Center. The overall goal of our GCID is to: i) leverage 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) utilize 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 dissect the genomic elements that confer the ability of pathogenic members of the Enterobacteriaceae and Enterococcaceae to associate with the human intestinal mucosa while also determining the host response to this association. Project 2 (PL: M. Estes, PhD) will leverage 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: D. Corry, MD) will test the hypothesis that fungal diversity, virulence, and individual innate immune responses to fungal burdens underlie persistent, treatment-resistant moderate to severe asthma in a new paradigm whereby fungal burden within the respiratory tract (?airway mycosis?) may have a causative role in development and persistence of allergic lung inflammation. 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 utilize human intestinal and lung organoid cultures along with niche-specific, defined microbial communities supplied by the Organoid and Minibioreactor Array Cultivation Core and a large collection of unique clinical samples and isolates, incorporating cutting edge, high-throughput sequencing strategies and technologies supplied by the Sequencing Technology (ST) Core. Paradigm-shifting discoveries, data, tools, and reagents will be disseminated to the infectious disease community by the Data Management Analysis and Resource Dissemination (DMARD) Core through a state of the art portal developed by DNAnexus. 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-based therapeutics and diagnostics, both for the pathogens in this proposal and a broad spectrum of mucosal infectious diseases that severely impact human health.

Public Health Relevance

New diagnostics and drugs to protect us from infectious diseases with the greatest health impact requires a thorough understanding of the infection process from the perspective of the pathogen, the host, and the ecological niche in which host-pathogen interaction occurs. Using new capabilities in genomic sequencing, unique clinically relevant samples from infected and uninfected individuals, and new model systems that allow us to study human infection, we will investigate disease mechanisms for several important bacterial, viral and fungal and parasite pathogens and discover new targets for diagnostics and drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI144297-01
Application #
9731077
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Lee, Eun MI
Project Start
2019-04-15
Project End
2024-03-31
Budget Start
2019-04-15
Budget End
2020-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030