# Pain and Neuro-immune Signaling in S. pyogenes pathogenesis

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $638,737

## Abstract

PROJECT SUMMARY
Pain (Dolor) is one of the four cardinal signs of inflammation, and often accompanies bacterial infections.
Nociceptor neurons are the peripheral sensory neurons that mediate pain, which densely innervate barrier
tissues including the skin and soft tissues that are exposed to pathogens. Streptococcus pyogenes is a leading
cause of necrotizing fasciitis, an invasive and life-threatening form of infection, in which pain occurs early and
“out of proportion” with other symptoms. We hypothesize that pain plays a major causative role in the
pathogenesis of S. pyogenes, by inducing neural mediated suppression of innate immune cell recruitment and
killing of bacteria. Here, we will determine: 1) The molecular mechanisms of pain during S. pyogenes infection,
with a focus on streptococcal pore-forming toxins streptolysin S (SLS) and streptolysin O (SLO), and 2) The
role of nociceptors and pain signaling in regulating neutrophil function and host defense against S. pyogenes.
We test the hypothesis that targeting pain signaling would lead to enhanced innate immune responses. Given
the importance of pain in the diagnosis of necrotizing fasciitis, and the widespread use of analgesics, our
findings connecting pain to S. pyogenes host defense could have important clinical implications. The two aims
of this study leverage the complementary skills of Dr. Chiu and Dr. Wessels, combining neurobiological,
immunological, and microbiological approaches to investigate the role of pain in host defense. In Specific Aim
1, we will determine the critical molecular mechanisms of pain production during S. pyogenes infection by two
clinical isolates. We use isogenic mutant bacterial strains and plasmid complementation strategies together
with neurobehavioral assays to determine whether SLS and SLO mediate S. pyogenes-induced pain. We will
determine whether the inflammasome and IL-1β are involved in neuronal recognition of pore-forming toxins or
pain signaling. In addition, we determine the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) in
impacting pain perception during S. pyogenes infection. In Specific Aim 2, we will determine how targeted
ablation of TRPV1+ nociceptors using RTX treatment or Trpv1-cre/DTA mice enhances host defenses against
S. pyogenes. We will determine how temporally and spatially controlled modulation of TRPV1+ neural activity
using optogenetic or DREADD strategies affects the outcome of S. pyogenes infection. We will also utilize
opioids to block central pain perception or Botulinum toxin to block peripheral pain signaling to determine which
neural component modulates immune responses against S. pyogenes. In our analysis, we elucidate the role of
nociceptor-derived neuropeptides such as CGRP in suppressing neutrophil phagocytosis and killing of S.
pyogenes. This study analyzes a significant link between induction of pain signaling, neural blockade of innate
immunity, and the potentiation of S. pyogenes bacterial pathoge...

## Key facts

- **NIH application ID:** 10206013
- **Project number:** 5R01AI130019-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Isaac Ming-Cheng Chiu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $638,737
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206013

## Citation

> US National Institutes of Health, RePORTER application 10206013, Pain and Neuro-immune Signaling in S. pyogenes pathogenesis (5R01AI130019-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10206013. Licensed CC0.

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