Journal Article

C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation

Gerhard, Ralf, Rakoff-Nahoum, Seth, Goldsmith, Jeffrey D., Shepherd, Amy, Rao, Meenakshi, Dong, Min, Liu, Min, Lee, Pyung-Gang, Zhao, Leo, Hurdle, Julian G., Manion, John, Wang, Siyu, Kuziel, Gavin A., Zhang, Jie, Yuan, Ke, Musser, Melissa A., Marreddy, Ravi K. R., Jin, Rongsheng

2023

Overview

Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections . The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization , but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes through receptors, including the Frizzled receptors (FZD1, FZD2 and FZD7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB stimulates the secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin, into peptidergic sensory neurons that express exogeneous diphtheria toxin receptor (an approach we term toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP or the SP receptor (neurokinin 1 receptor) show reduced pathology in both models of caecal TcdB injection and CDI. Blocking SP or CGRP signalling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or with hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.

• Publisher: Nature Publishing Group
• Subject: Animals / Antibiotics / Bacterial Toxins - administration & dosage / Bacterial Toxins - pharmacology / Calcitonin / Calcitonin gene-related peptide / Calcitonin Gene-Related Peptide - antagonists & inhibitors / Calcitonin Gene-Related Peptide - metabolism / Cecum - drug effects / Cecum - metabolism / Chondroitin sulfate / Clostridioides difficile - pathogenicity / Clostridium Infections - microbiology / Colon / Diphtheria / Diphtheria toxin / Edema / Frizzled protein / Histopathology / Infections / Inflammation / Inflammation Mediators - metabolism / Mice / Neurogenic Inflammation - chemically induced / Neurogenic Inflammation - microbiology / Neurogenic Inflammation - pathology / Neurokinin / Neurokinin NK1 receptors / Neurons / Neurons, Afferent - drug effects / Neurons, Afferent - microbiology / Neurons, Afferent - pathology / Neuropeptides / Neutrophils / Pathogenesis / Pathology / Pericytes / Pericytes - drug effects / Pericytes - microbiology / Pericytes - pathology / Proteoglycans / Receptors / Receptors, Neurokinin-1 - metabolism / Sensory neurons / Signal Transduction - drug effects / Substance P / Substance P - antagonists & inhibitors / Substance P - metabolism / Sulfates / Toxins