# Protective mechanisms of the gut Bacteroidales

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $454,780

## Abstract

Project Summary
Our long-term objectives are to understand genetic and phenotypic properties that allow the
abundant human gut Bacteroidales species to survive in the host over its lifetime. In this proposal,
we will build upon our work studying antibacterial toxins produced by the gut Bacteroidales that
they use to antagonize other members of ecosystem. We will study important protective
responses mounted by these bacteria upon exposure to antibacterial toxins and other stressors
they encounter in the gut microbiota. We found that the genes of an unusual ECF-type sigma
factor/antisigma factor pair, named EcfO-Reo, are induced upon exposure of Phocaeicola
vulgatus to toxins and other stress-inducing compounds. The ensuing pleiotropic response
protects these bacteria from various stressors that perturb the outer membrane. efcO-reo and the
genes of its regulon are among the most highly expressed in vivo. The genes of this regulon
include those encoding three families of proteins with unknown functions: the NigD proteins, a
family of outer membrane porins, and proteins involved in the synthesis of long LPS. Our
preliminary data suggest that these genes are regulated in different manners and provide distinct
mechanisms of protection. In Aim 1, we will use a transcriptional reporter and phenotypic analyses
to identify microbial, host and abiotic stressors that induce expression of the ecfO-reo operon and
determine if induction of the response protects the bacteria from those stressors. In Aim 2, we will
determine the molecular basis of long LPS (O-antigen) synthesis and the protection it confers to
diverse stressors. In Aim 3, we will use genetic and phenotypic analyses combined with unbiased
approaches to identify the protective functions of the NigD family of proteins. These proteins are
are released in outer membrane vesicles when the EcfO regulon is induced by outer membrane
perturbations. In Aim 4, we will study a family of outer membrane proteins that are highly
upregulated when the EcfO-Reo operon is induced. We will use a combination of techniques to
identify the unique mechanism of regulation and the contribution of these OMPs to the EcfO-Reo-
induced protective response. For all aims, we will study the contribution of the different arms of
the protective response to the fitness of the bacteria in the gnotobiotic mouse gut. The knowledge
gained from this proposal will greatly increase our understanding of the molecular mechanisms
that this order of bacteria use to survive in the human gut microbiota when exposed to various
stressors of host, microbial and xenobiotic origin.

## Key facts

- **NIH application ID:** 10883390
- **Project number:** 2R01AI093771-10A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** LAURIE E COMSTOCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $454,780
- **Award type:** 2
- **Project period:** 2012-07-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883390

## Citation

> US National Institutes of Health, RePORTER application 10883390, Protective mechanisms of the gut Bacteroidales (2R01AI093771-10A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10883390. Licensed CC0.

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