Contact-dependent interbacterial responses modulate intestinal colonization by Bacteroides species

Project Summary/Abstract
The diverse group Bacteroidales is a predominant component of human intestinal microbiota, linked to numerous
disease processes. Manipulation of Bacteroidales at the genus and species level holds therapeutic potential, but
requires a more detailed understanding of the intestinal ecosystem. Bacteroides spp. genomes encode
polysaccharide utilization loci (PUL), allowing enzymatic breakdown, membrane transport, and utilization of
complex carbohydrates. Bacteroides spp. antagonize one another within the intestinal environment by delivering
toxic effectors via contact-dependent type VI secretion systems (T6SS), resulting in altered capacities for
colonization and persistence. The central hypothesis of this proposal is that contact among Bacteroides spp.
results in dynamic adaptive responses that alter cellular behavior and contribute to persistence in the intestinal
environment. The proposed experiments will discover contact-dependent proteomic responses important for
competition within Bacteroides communities using cutting-edge proteomics technology (Aim 1). Molecular
mechanisms of two known contact-dependent responses, altered polysaccharide utilization (Aim 2) and T6SS-
mediated delivery of hcp-effector fusions (Aim 3), will be elucidated and translated to competitive growth and
intestinal colonization in a gnotobiotic mouse model. A long-term research goal is to understand mechanisms
underlying interbacterial interactions among intestinal symbionts for the development of targeted therapeutics.
The candidate for this career development award is an M.D./Ph.D. physician scientist with board certification in
anatomic and clinical pathology. The research proposed in this grant application will be conducted under the
mentorship of Dr. Joseph Mougous, Professor of Microbiology, and Dr. Matthew Yeh, Professor of Pathology.
The candidate will join faculty in a department with ample clinical resources for development of specialized
expertise in gastrointestinal pathology, established NIH-funded investigators and research infrastructure, and a
track record of strong support for physician scientists. The candidate is committed to a career as a physician
scientist and seeks further scientific training. Career development plans include participation in relevant local
and national meetings, advanced didactics and workshops to gain expertise in commensal bacteriology, build
research communication and grant writing skills, and develop leadership and management skills. This mentored
clinical scientist development award will facilitate the candidate’s transition to become a competitive NIH-funded
independent investigator.

Grant Number: 5K08AI159619-06
NIH Institute/Center: NIH
Principal Investigator: Dustin Bosch