# Unravelling MyD88-dependent and independent mucosal immunity to Toxoplasma

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO · 2024 · $439,698

## Abstract

Project Summary/Abstract
The long-term objective of this proposal is to understand inductive and effector mechanisms of host
defense in the intestinal mucosa. We use as a tool the intracellular protozoan Toxoplasma gondii, an orally
acquired opportunistic pathogen inducing strong protective Th1- and IFN--based immunity and that is a
significant health hazard in immunocompromised populations. Signaling through the adaptor molecule
MyD88 is necessary for optimal initiation of immunity and resistance to this pathogen. While IL-1 family
cytokine receptors use MyD88, the primary role of this signaling adaptor during T. gondii infection is
believed to be in Toll-like receptor (TLR) signaling. Nevertheless, the particular TLR involved (TLR11/12)
are not expressed in humans and indeed many other species, indicating presence of MyD88-independent
pathways of immune initiation. Such pathways are also present in mice, insofar as infection of MyD88
knockout animals triggers robust, albeit delayed, Th1 responses in the intestinal mucosa. Additionally,
MyD88 knockout mice can be vaccinated against lethal challenge with orally inoculated Toxoplasma. Open
questions remain regarding the role of MyD88 in specific cell types and in the context of the intestine how
the microbiota influences MyD88-dependent and MyD88-independent immunity during Toxoplasma
infection. The central hypothesis underpinning our research is that MyD88-dependent pathways and
MyD88-independent pathways work together to provide optimal immune initiation during infection. We will
address this hypothesis focusing on interactions between cells of the lamina propria, Toxoplasma and the
host microbiota. Using our hypothesis to guide us, we will pursue three specific aims. Aim 1: Determine
the role of intestinal epithelial cells in initiation of immunity and control of Toxoplasma. Using intestinal
organoids we will examine how epithelial cells respond to infection, and how this impacts responses in the
lamina propria compartment. The influence of epithelial MyD88 in immunity to T. gondii will be determined.
Aim 2: Identify how MyD88 impacts innate lymphoid cell (ILC) function during Toxoplasma infection. The
activity of ILC, with a focus on ILC1 and ILC3, will be examined using mouse strains deficient in ILC
populations and strains with deletion of MyD88 in ILC. Aim 3: Determine the influence of MyD88 expression
on generation of mucosal T cell effector and memory function. The requirement for MyD88 in lamina propria
T cells will be determined with regard to short term effector function and long-term memory function. The
importance of this research is that it will significantly extend and deepen our understanding of mechanisms
of resistance to Toxoplasma within the mucosal immune system, which is critical to understanding mucosal
host defense in humans. The ultimate impact of this research is that it can be expected to identify novel
parasite and host targets for promoting resistance and immunity dur...

## Key facts

- **NIH application ID:** 10868540
- **Project number:** 5R01AI139628-07
- **Recipient organization:** UNIVERSITY OF NEW MEXICO
- **Principal Investigator:** ERIC Y DENKERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $439,698
- **Award type:** 5
- **Project period:** 2018-05-18 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868540

## Citation

> US National Institutes of Health, RePORTER application 10868540, Unravelling MyD88-dependent and independent mucosal immunity to Toxoplasma (5R01AI139628-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10868540. Licensed CC0.

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