# Deciphering the logic of glycolipid signaling at the host-microbiome interface

> **NIH NIH R00** · HARVARD MEDICAL SCHOOL · 2021 · $249,000

## Abstract

Project Summary/Abstract
Humans are densely colonized with symbiotic bacteria – collectively referred to as the microbiome – that
modulate physiology, for example through potent small molecules. Extensive efforts have both identified crucial
roles of the microbiome in healthy human biology and linked composition of the microbiome and its associated
small molecules to diseases ranging from autoimmune diseases to neurological disorders. The underlying
molecular mechanisms of host-microbiome interactions, however, are largely undefined, impeding the
development of therapeutic interventions for microbiome-associated diseases.
 Recent advances in high-throughput functional genomics methods to systematically probe the functions
of human and bacterial genes, such as CRISPR-based genetic screens, now in principle enable systematic
studies into the molecular mechanisms of host-microbiome interactions. To achieve their potential for
microbiome biology, such systematic screening methods must be implemented and validated in model systems
that recapitulate phenotypes relevant to host-microbiome interactions; once implemented, they represent
powerful tools to identify genes involved in producing these phenotypes.
 This proposal describes the development of functional genomics approaches for primary human
dendritic cells, a model system for interactions between the microbiome and the human immune system, and
the application of these approaches to the identification of host receptors and physiological roles of two classes
of bacterial glycolipids, capsular polysaccharides and lipopolysaccharides. Both classes are highly abundant in
the microbiome and individual examples have suggested central roles for these molecules in modulating
immune function. For example, individual capsular polysaccharides are known to induce differentiation of
regulatory T-cells, and lipopolysaccharides are ligands for innate immune cells and elicit varying responses
ranging from inflammation to immunosuppression. In this proposal, the development of new bacterial strain
libraries with controlled variations in glycolipid structure is combined with functional genomics approaches to
conduct structure-function analyses of the effects of glycolipids on immune cells and to identify the host
receptors and signaling pathways that mediate these effects. This dissection of the mechanisms underlying
glycolipid signaling at the host-microbiome interface will improve understanding of the role of the microbiome in
modulating function and maturation of the immune system.
 The approaches described in this proposal will be similarly applicable to study the roles of other
microbiome-derived molecules, human receptors implicated in microbiome diseases, or individual bacterial
strains. Altogether, this proposal will both provide new insight into the biology of the microbiome and establish
generally applicable approaches to decipher mechanisms of host-microbiome interactions.

## Key facts

- **NIH application ID:** 10332881
- **Project number:** 4R00GM130964-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Marco Jost
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2019-07-16 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10332881

## Citation

> US National Institutes of Health, RePORTER application 10332881, Deciphering the logic of glycolipid signaling at the host-microbiome interface (4R00GM130964-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10332881. Licensed CC0.

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