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C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation

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

Nature (London), 2023-10, Vol.622 (7983), p.611-618 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation
Autor: Manion, John ; Musser, Melissa A ; Kuziel, Gavin A ; Liu, Min ; Shepherd, Amy ; Wang, Siyu ; Lee, Pyung-Gang ; Zhao, Leo ; Zhang, Jie ; Marreddy, Ravi K R ; Goldsmith, Jeffrey D ; Yuan, Ke ; Hurdle, Julian G ; Gerhard, Ralf ; Jin, Rongsheng ; Rakoff-Nahoum, Seth ; Rao, Meenakshi ; Dong, Min
Assuntos: 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
É parte de: Nature (London), 2023-10, Vol.622 (7983), p.611-618
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J.M. and M.D. conceived the project. J.M., M.A.M., G.A.K., A.S., M.L., S.W., M.R., and M.D. participated in experimental design, execution, and data analysis. G.A.K., M.L., A.S., and S.W. contributed equally. Cultured DRG studies were performed by J.M. and L.Z. Cultured pericyte studies were performed by J.M. and M.L. J.Z. provided essential training and established surgical models. M.A.M. and M.R. performed most of the immunohistochemistry and confocal imaging studies with assistance from J.M. and A.S. J.M., G.A.K. and S.R.-N performed microbiome analyses and in vitro analyses of C. difficile. J.M. conceived the toxogenetic approaches. P.G.L designed and purified the toxogenetic proteins. K.Y. helped with pericyte culture and analysis. J.D.G. provided human tissue samples. R.G. and R.J designed and provided essential reagents. R.M. and J.G.H. prepared C. difficile spores and strains. M.R. and M.D. supervised and coordinated the work.
Author Contributions
These authors contributed equally
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation

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

England: Nature Publishing Group

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