# Project 1: Innate immune responses triggered by Listeria monocytogenes

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $530,768

## Abstract

Project Summary/Abstract (Project 1, Portnoy)
This proposal is Project 1 within a P01 renewal, entitled “Intracellular pathogens and innate immunity.” 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 concentrated on macrophage transcriptional
responses to infection and learned that L. monocytogenes escapes from a phagosome and secretes a
conserved and essential small signaling molecule called c-di-AMP that activates the transcription of the host
type I interferon response. In collaboration with the Vance lab, we identified STING as the host cell receptor
for both c-di-AMP and other c-di-nucleotides. In Aim 1, we propose to extend these studies, using bacterial
mutants that either synthesize or secrete altered levels of c-di-AMP in combination with mice and host cells
that have specific STING mutations that alter downstream signaling. In Aims 2 and 3, we begin to explore
the role of post-transcriptional host responses including ubiquitylation of both bacterial and host proteins
and the role played by autophagy. In Aim 2, we follow-up on preliminary data showing that L.
monocytogenes is subject to autophagy at the phagosome, but circumvents it using two determinants, PlcA
and ActA. We show that a double PlcA/ActA mutant is trapped by what appears to be LC3-associated
phagocytosis (LAP). We will use bacterial and host mutants to determine if this is in fact LAP, how the
bacteria avoid it, and finally, what is the role of LAP avoidance during infection and immunity. In Aim 3, we
propose using mass spectrometry-based and bioinformatic tools, available in Core C, to identify the
bacterial and host proteins that are ubiquitylated, and high throughput genetic screens to identify the host
proteins that mediate ubiquitylation.

## Key facts

- **NIH application ID:** 9977105
- **Project number:** 5P01AI063302-17
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** DANIEL A PORTNOY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,768
- **Award type:** 5
- **Project period:** 2004-12-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977105

## Citation

> US National Institutes of Health, RePORTER application 9977105, Project 1: Innate immune responses triggered by Listeria monocytogenes (5P01AI063302-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977105. Licensed CC0.

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