# Central role for skin sensory neurons in anti-helminth immunity

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2024 · $203,125

## Abstract

Most soil transmitted helminth (STH) species have skin-penetrating larval stages that facilitate chronic human
infections causing significant morbidity worldwide. Although these infectious larvae (iL3) are known to release
a wide array of excretory-secretory products (ES) that damage skin and mucous membranes human hosts have
very little awareness of this process. Rare case reports indicate itch, but otherwise most people do not know
they are infected until there are gastrointestinal symptoms or anemia. This suggests that the pain-sensing
neurons in the skin may be actively silenced by worm ES. While the activity of transient receptor potential
channel vanilloid 1 (TRPV1)-expressing sensory neurons is known to contribute to host protective immunity
against microbial and fungal pathogens, it is entirely unknown whether these skin neurons influence immunity
against STH infection. This major gap in knowledge is likely because current experimental methods use needle
injection to deliver iL3, which bypasses neurons that innervate the epidermal and dermal layers of skin. To
address this issue, we have developed a natural model of STH infection where the foot of a mouse is transiently
exposed to a saline bath of iL3, allowing natural penetration. Our preliminary studies show that significantly fewer
iL3 penetrate the skin of wild-type mice in a second exposure to iL3, indicating that resistance develops.
Optogenetics uses blue light to activate the cation channel rhodopsin (CHR2) that is expressed by specific cell
populations expressing the cre protein in transgenic mice. When we used this technique to activate TRPV1+
cells, we found a significant reduction in iL3 skin penetration suggesting that sensory neuron activity may
contribute to host protective mechanisms. Further, iL3 ES seem to reduce the ability of neurons to respond to
the TRPV1 agonist capsaicin. Thus, our overarching goal is to combine this parasite infection model system
with sensory neuroscience methods that non-invasively activate specific populations of pain or itch-sensing
neurons to investigate how neurons control the ability of iL3 to penetrate the skin. Aim 1 tests whether
optogenetic activation of nociceptors or other TRPV1+ cells augments host resistance against STH
through induction of skin neuropeptides, inflammatory cells and/or Type 2 and Type 17 cytokines. Also,
based on our data showing that treatment with ES products impairs sensory neuron activation, experiments in
Aim 2 seek to identify the molecules in ES products that suppress sensory neuron activation and
determine whether this equates with blunted behavioral responses to itchy or painful stimuli. Taken
together, this R21 stands to break new ground in understanding the neuroimmunology of host protection against
parasitic helminths and may reveal novel bioactive molecules with multidisciplinary therapeutic potential.

## Key facts

- **NIH application ID:** 10764948
- **Project number:** 5R21AI171740-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** De'Broski R Herbert
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $203,125
- **Award type:** 5
- **Project period:** 2023-01-17 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764948

## Citation

> US National Institutes of Health, RePORTER application 10764948, Central role for skin sensory neurons in anti-helminth immunity (5R21AI171740-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10764948. Licensed CC0.

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