C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation

John Manion, Melissa A. Musser, Gavin A. Kuziel, Min Liu, Amy Shepherd, Siyu Wang, Pyung-Gang Lee, Leo Zhao, Jie Zhang, Ravi K. R. Marreddy, Jeffrey D. Goldsmith, Ke Yuan, Julian G. Hurdle, Ralf Gerhard, Rongsheng Jin, Seth Rakoff-Nahoum, Meenakshi Rao () and Min Dong ()
Additional contact information
John Manion: Boston Children’s Hospital
Melissa A. Musser: Boston Children’s Hospital and Harvard Medical School
Gavin A. Kuziel: Harvard Medical School
Min Liu: Boston Children’s Hospital
Amy Shepherd: Boston Children’s Hospital and Harvard Medical School
Siyu Wang: Boston Children’s Hospital
Pyung-Gang Lee: Boston Children’s Hospital
Leo Zhao: Boston Children’s Hospital
Jie Zhang: Boston Children’s Hospital
Ravi K. R. Marreddy: Texas A&M Health Science Center
Jeffrey D. Goldsmith: Boston Children’s Hospital
Ke Yuan: Boston Children’s Hospital and Harvard Medical School
Julian G. Hurdle: Texas A&M Health Science Center
Ralf Gerhard: Hannover Medical School
Rongsheng Jin: University of California Irvine
Seth Rakoff-Nahoum: Harvard Medical School
Meenakshi Rao: Boston Children’s Hospital and Harvard Medical School
Min Dong: Boston Children’s Hospital

Nature, 2023, vol. 622, issue 7983, 611-618

Abstract: Abstract Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections1,2. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization3–6, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06607-2

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