Overview

HOST, PATHOGEN AND THE MICROBIOME: DETERMINANTS OF DISEASE OUTCOME

The studies proposed in this application will explore the dynamic interactions between high-priority pathogens, hosts, their microbiota, the immune system, and the environment, with the goal to provide a comprehensive understanding of the determinants of infectious disease. This work will be carried out by a highly collaborative group of investigators at the University of Maryland School of Medicine (UMSOM), several of whom are pioneers in the field of microbial genomics and have continued to lead research in this area for nearly two decades. The Research Projects described herein: (i) are hypothesis-driven, (ii) can only be accomplished through the application of high-throughput "-omics" technologies, and (iii) will both stimulate, and be enhanced by, ongoing technology development within our research groups and Cores. We will characterize unique sets of samples from human subjects, when possible, as well as relevant animal or cell culture models of disease, as appropriate to each project.

Bacterial Project: Examination of enteric pathogens with multi-omic approaches. The project will examine the potential interactions between enteric pathogens, hosts and the microbiota and we will characterize these interactions during infection with Vibrio cholerae and enterotoxigenic Eschericha coli (ETEC). We will take advantage of two ongoing human challenge trials to assess the population dynamics of these pathogens during human passage, the changes in the structure and function of the gastrointestinal microbiota following vaccination and exposure to wild-type pathogens, and the transcriptional impact of host-pathogen interactions in complex system. The expected outcomes of this project will be a greater understanding of the complex interactions and regulatory mechanisms of these enteric pathogens as well as the identification of novel potential targets for vaccinology.

Fungal Project: Genomic analysis of fungal pathogens. This project will combine transcriptomics, well-established animal and cell culture models and fungal genetics to systematically and comprehensively analyze the host-pathogen interactions of the phylogenetically distinct pathogenic fungi, Candida albicans, Aspergillus fumigatus, and Mucormycosis species. The expected outcome from this project will be a deeper understanding of fungal virulence, the host response to fungal infections and a catalog of conserved genes and pathways in these three pathogenic fungi and their hosts that are involved in the process of infection. The ultimate goal of this research is to exploit this information to design new anti-fungal drugs that specifically target conserved pathways of the pathogenic fungi with minimal host toxicity.

Parasite Project: Integrated genomics research in parasitic tropical diseases. This project will examine the genomic variation in natural populations, and the unappreciated interactions between host, parasites and microbiota will be exploited to develop new strategies for control and prevention of malaria and filariasis. This project will combine genomics-based studies of parasite population dynamics (Plasmodium), transcriptomics analysis of pathogen and hosts (Brugia), access to clinical cohorts undergoing malaria vaccine trials (Plasmodium), and animal models of filariasis (Brugia) to obtain new information related to drug resistance, immunity in natural populations, and possible therapeutic targets for two parasitic pathogens that together account for considerable world-wide morbidity and mortality.