# The intersection of innate and adaptive immunity to intracellular pathogens

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $2,325,406

## Abstract

Project Summary/Abstract (Overall)
This application is a competitive renewal of a program project grant entitled, “The intersection of innate and
adaptive immunity to intracellular pathogens.” A major goal of this P01 is to identify and characterize innate
immune pathways that are triggered, avoided, or manipulated by intracellular pathogens and to determine
the role of these pathways during infection and immunity. More specifically, in this P01 we focus on the
microbiology and immunobiology of three diverse facultative intracellular bacterial pathogens; Listeria
monocytogenes, Legionella pneumophila, and importantly, M. tuberculosis. An overall theme of this
application is that the innate immune system detects key metabolites and virulence activities of intracellular
bacterial pathogens, including cytosolic invasion or access via dedicated bacterial secretion systems. For
example, all three pathogens under investigation activate STING, either by direct secretion of a cyclic-di-
nucleotide (CDN) or by activation of host cell cGAS in response to bacterial DNA, to activate STING,
culminating in critical host responses including activation of a type I IFN and autophagy. In Project 1,
Portnoy extends his studies on the roles of c-di-AMP and STING by examining how c-di-AMP secretion
affects L. monocytogenes pathogenesis and dissemination to the placenta and brain during an oral model of
infection. In Project 2, Cox asks how M. tuberculosis uses its ESX-1 type VII secretion system to perforate
phagosomal membranes, activate STING and induce production of type I IFN, which promotes infection, but
also activates ubiquitin-mediated autophagy responses, which serves to limit infection. However, while type
I IFNs are generally accepted to play a crucial role in orchestrating anti-viral immunity, the roles of type I
IFNs in the responses to bacteria are complex and often exacerbate infection by bacterial pathogens. In
Project 3, Vance presents preliminary data suggesting that type I IFN-dependent induction of the
interleukin-1 receptor antagonist (IL-1Ra) is an important mechanism by which type I IFNs exacerbate
bacterial infections. We also explore the idea that CDNs are just one example of immunostimulatory
bacterial metabolites by analyzing two other bacterial metabolites that lead to the activation of what are
classified as innate or invariant T-cells, including MAIT cells and Vg9Vd2 T-cells. We will ascertain the
relevance of these metabolites during L. monocytogenes and M. tuberculosis infection (Projects 1, 2 and
4). In Project 4, Stanley propose to follow up on her preliminary data showing the CDN-based protein
vaccines result in a robust and durable tuberculosis vaccines especially when introduced intranasally that is
associated with induction of a protective Th17 response. Stanley proposes to evaluate a number of vaccine
strategies using CDNs in combination with modified BCG and L. monocytogenes-based vectors.

## Key facts

- **NIH application ID:** 10885123
- **Project number:** 5P01AI063302-21
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** DANIEL A PORTNOY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,325,406
- **Award type:** 5
- **Project period:** 2004-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885123

## Citation

> US National Institutes of Health, RePORTER application 10885123, The intersection of innate and adaptive immunity to intracellular pathogens (5P01AI063302-21). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10885123. Licensed CC0.

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