# The Intracellular Pathogen Response Triggers Defense Against Co-evolved Pathogens

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $357,747

## Abstract

Project Summary
 Infectious diseases impose a significant burden on human health, with epithelial cells on the front lines
of attack by disease-causing microbes that can invade and replicate inside of these cells. In addition to
diseases such as diarrhea and pneumonia caused by pathogens, inappropriate activation of defense pathways
in epithelial cells can lead to inflammatory disease. Therefore, it is critical learn more about epithelial defense
against intracellular pathogens. In particular, little is known about defense against the Microsporidia phylum of
fungal-related intracellular parasites, 14 of which can infect and cause disease in humans, most commonly
infecting intestinal epithelial cells. We have developed a convenient whole-animal model for studying defense
against microsporidia through characterization of natural intestinal infection in the nematode C. elegans. Our
long-term goal is to dissect the mechanisms by which epithelial cells defend against co-evolved intracellular
pathogens like microsporidia. Closing this gap in our understanding will provide new insights for treating
infectious disease and inflammatory disorders. Our central hypothesis is that attack from co-evolved pathogens
causes expansion and diversification of host genes to become ‘species-specific’ although these genes may
control conserved immune pathways. The objective here is to characterize the species-specific pals gene
family, which expanded to 39 pals genes in C. elegans, whereas there is only one pals gene in humans.
Virtually nothing is known about PALS protein structure or biochemical function in any system, although they
have been connected to ubiquitin ligases through sequence analysis and genetic studies in C. elegans.
 We found PALS-22 and PALS-25 to be key regulators of a common transcriptional response to natural
microsporidia and viral infections in C. elegans that we call the Intracellular Pathogen Response or IPR. The
IPR appears to define an entire physiological program and our forward genetic screens identified PALS-22 as
a negative regulator and PALS-25 as a positive regulator of the IPR. Loss of PALS-22 leads to enhanced
immunity against intracellular pathogens, increased RNA interference, as well as fitness consequences such
as delayed development, all of which depend on PALS-25. In Specific Aim 1 we will characterize the
relationship between gene expression and immune responses regulated by PALS-22 and PALS-25, identify
the tissues where they act, and define the stage of microsporidia they target. In Specific Aim 2 we will
recombinantly express PALS-22 and PALS-25 proteins to characterize their interaction, as well as their
structure using X-ray crystallography and cryo EM. In Specific Aim 3 we will analyze the role of other PALS
proteins, RNAi machinery and identify new regulators of the IPR. The approach is innovative as it focuses on
uncharacterized proteins that regulate a novel form of epithelial immunity. The proposed research is signi...

## Key facts

- **NIH application ID:** 10468643
- **Project number:** 5R01GM114139-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Emily R Troemel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $357,747
- **Award type:** 5
- **Project period:** 2015-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468643

## Citation

> US National Institutes of Health, RePORTER application 10468643, The Intracellular Pathogen Response Triggers Defense Against Co-evolved Pathogens (5R01GM114139-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468643. Licensed CC0.

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