# MyD88-independent resistance to Toxoplasma in the intestine

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO · 2021 · $376,103

## Abstract

Project Summary/Abstract
The long-term objective of this proposal is to understand induction and effector mechanisms of immunity
in the absence of signaling adaptor MyD88. We use as a tool the intracellular protozoan Toxoplasma gondii,
an orally acquired opportunistic pathogen that normally induces strong protective Th1- and IFN-γ-based
immunity. Toxoplasma can activate mouse immunity through an MyD88-dependent TLR11/12 pathway. Yet,
humans lack these TLR and populations deficient in MyD88 expression retain resistance to all but a limited
number of bacterial infections. Therefore, immune pathways that do not involve MyD88 are important to
understand. We have found that MyD88 knockout mice are capable of generating Th1-like immunity during
Toxoplasma infection, indicating that alternative pathways for immune initiation are active in the mouse
model. In addition, MyD88 knockout animals can be vaccinated against lethal infection with orally inoculated
T. gondii. The cell and molecular mechanisms underpinning MyD88-independent immunity are
uncharacterized. The central hypothesis driving this research proposal is that the mouse immune system
is equipped to generate protective immunity to Toxoplasma using MyD88-independent pathways of
resistance. We more generally hypothesize that this is important for understanding human disease based
upon overall resistance to infections in the absence of MyD88. Three Specific Aims will be used to
understand MyD88-independent immunity during infection. Aim 1: Determine how T cells are activated in
the absence of MyD88 signaling in the mucosal response to Toxoplasma. We will investigate cytokine
requirements for MyD88-independent generation of IFN-γ-positive T cells and characterize the phenotype
and specificity of these cells. Aim 2: Determine the impact of MyD88 deficiency on gut microbicidal effector
functions. We will examine how deficiency in this signaling adaptor affects recruitment and function of anti-
microbial effector cells in the intestinal mucosa following Toxoplasma infection. Aim 3: Determine how
vaccination with an avirulent Toxoplasma strain triggers MyD88-independent protective immunity in the
intestinal mucosa. We will employ a nonproliferating Toxoplasma strain to determine how T. gondii induces
resistance to lethal oral challenge in a model where immunity can be triggered without complications
associated with parasite-induced tissue damage. The importance of this research is that it will significantly
extend and deepen our understanding of induction and effector mechanisms of immunity in the absence of
MyD88, which is critical to understanding 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
during infectious disease.

## Key facts

- **NIH application ID:** 10145582
- **Project number:** 5R01AI139628-04
- **Recipient organization:** UNIVERSITY OF NEW MEXICO
- **Principal Investigator:** ERIC Y DENKERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,103
- **Award type:** 5
- **Project period:** 2018-05-18 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145582

## Citation

> US National Institutes of Health, RePORTER application 10145582, MyD88-independent resistance to Toxoplasma in the intestine (5R01AI139628-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10145582. Licensed CC0.

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