# Nervous system control of immunity to C. difficile

> **NIH NIH U19** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $342,524

## Abstract

Project Summary (Project 3)
Clostridioides difficile is the leading nosocomial infection in the US, and is characterized by recurrent infection
and poor generation of antibacterial antibody responses. Identifying how C. difficile evades the adaptive immune
system is critical to develop rational treatments for patients with C. difficile infections and to prevent recurrence.
Interestingly, the major risk factors for C. difficile infection (broad spectrum antibiotic usage, proton pump inhibitor
treatment, inflammatory bowel disease) all result in either a loss or dysfunction of nerves in the gut. Infection
with C. difficile also results in a profound loss of nerves in the colon of mice. It is currently unknown if a loss of
innervation in the gut can be a primary driver of CDI susceptibility. Additionally, there is increasing awareness of
the outsized role of the nervous system in promoting immune function. Sensory nerves directly sense pathogens,
cellular damage, and noxious chemicals in order to allow organisms to respond and eliminate damage.
Adrenergic nerves in the spleen and lymph nodes are necessary for optimal B cell responses to vaccination and
infection. We posit that sensory nerve signaling from the site of infection or vaccination communicates through
the nervous system to the adrenergic nerves in lymphoid organs to promote immune responses. Given the
important role for neuronal signaling in promoting immunity, is it perhaps unsurprising that numerous pathogens
across a wide diversity of species specifically target the nervous system. Significantly, the C. difficile exotoxins
TcdA and TcdB both have neuronal activity in addition to their well described function in the inactivation of Rho
GTPases by glucosylation. In collaboration with Dr. Mark Lang, we have found that TcdA inhibits the
development of antigen-specific antibody responses during vaccination, and this inhibition was dependent upon
sensory nerve signaling; desensitization of these nerves during vaccination restored antibody responses even
in the presence of TcdA. Combined with our finding that CDI induces profound neuronal loss in the gut, We
hypothesize that TcdA and TcdB manipulation and deletion of nerves is necessary for C. difficile infection and
immune evasion. In Specific Aim 1 we will determine the role of neuronal signaling in C. difficile infection and
immune evasion. In Specific Aim 2 we will identify the mechanism by which TcdA hyperactivation of sensory
nerves impairs humoral immunity. These studies will advance the C. difficile vaccination field by revealing specific
mechanisms that limit successful humoral immune responses to vaccination and infection, and determining
whether neuropreservation is a critical correlate of protection for CDI.

## Key facts

- **NIH application ID:** 10892834
- **Project number:** 5U19AI174994-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Maureen Cox
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $342,524
- **Award type:** 5
- **Project period:** 2023-07-25 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892834

## Citation

> US National Institutes of Health, RePORTER application 10892834, Nervous system control of immunity to C. difficile (5U19AI174994-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10892834. Licensed CC0.

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