# Project 1: Listeria metabolites and innate immunity

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2022 · $558,261

## Abstract

Project Summary/Abstract (Project 1, Portnoy)
This proposal is Project 1 within a P01 renewal, entitled “The intersection of innate and adaptive immunity to
intracellular pathogens.” A central problem that we address is how intracellular pathogens are recognized
by the host innate immune system and how multiple signals are integrated to induce an appropriate
response, and conversely, how pathogens avoid and/or manipulate host responses to promote their
pathogenesis. In Project 1, we have chosen to approach this problem by continuing a detailed analysis of
Listeria monocytogenes, a facultative intracellular, food-borne pathogen that has been studied for decades
as a model system with which to dissect basic aspects of infection & immunity. Previously, we discovered
that L. monocytogenes secretes c-di-AMP which binds to and activates host STING leading to a type I
interferon response. In Aim 1, we exploit a newly developed oral model of listeriosis where we find that
bacterially secreted c-di-AMP induces a STING-dependent host protective response. We propose to
analyze how STING provides protection and test the hypothesis that STING also promotes dissemination to
the placenta and brain. In Aims 2 and 3, we begin to explore the idea that c-di-AMP might be just one
example of the principle that small bacterial metabolites play important roles in shaping host immunity. L.
monocytogenes is a riboflavin requiring microorganism, and we explore the hypothesis that that this
nutritional requirement allows the bacteria to avoid activation of mucosal-associated invariant T-cells (MAIT
cells), which are innate T-cells stimulated by a modified intermediate of riboflavin biosynthesis. In
preliminary data, we introduced five Bacillus subtilis genes (ribDEAHT) into L. monocytogenes converting it
into a riboflavin-synthesizing bacterium and are now poised to test our hypothesis and learn about the role
of MAIT cells during bacterial infection and immunity. We also propose to explore the activation of the
dominant gamma delta T-cell in humans (Vg9Vd2 T-cells). These cells are activated by an intermediate of
bacterial isoprenoid biosynthesis (HMBPP). Our ultimate goal is to determine the importance of this innate
immune pathway during infection of primates (human and non-human). Here we propose to construct
bacterial mutants that either fail to make HMBPP or make more of it to examine how bacterial HMBPP is
detected during infection in tissue culture models. We further propose to collaborate with the Cox lab
(Project 2) to explore the importance of HMBPP during M. tuberculosis infection and immunity.

## Key facts

- **NIH application ID:** 10400182
- **Project number:** 5P01AI063302-19
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** DANIEL A PORTNOY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $558,261
- **Award type:** 5
- **Project period:** 2004-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400182

## Citation

> US National Institutes of Health, RePORTER application 10400182, Project 1: Listeria metabolites and innate immunity (5P01AI063302-19). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10400182. Licensed CC0.

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