C. difficile intoxicates neurons and pericytes to drive neurogenic inflammation.

Autor: Manion J; Department of Urology, Boston Children's Hospital, Boston, MA, USA.; Department of Surgery, Harvard Medical School, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Musser MA; Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Kuziel GA; Department of Microbiology, Harvard Medical School, Boston, MA, USA.; Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Liu M; Department of Urology, Boston Children's Hospital, Boston, MA, USA.; Department of Surgery, Harvard Medical School, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Shepherd A; Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Wang S; Department of Urology, Boston Children's Hospital, Boston, MA, USA.; Department of Surgery, Harvard Medical School, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA.; Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Lee PG; Department of Urology, Boston Children's Hospital, Boston, MA, USA.; Department of Surgery, Harvard Medical School, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Zhao L; Department of Urology, Boston Children's Hospital, Boston, MA, USA.; Department of Surgery, Harvard Medical School, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Zhang J; Department of Urology, Boston Children's Hospital, Boston, MA, USA.; Department of Surgery, Harvard Medical School, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Marreddy RKR; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA., Goldsmith JD; Department of Pathology, Boston Children's Hospital, Boston, MA, USA., Yuan K; Division of Pulmonary Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Hurdle JG; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA., Gerhard R; Institute of Toxicology, Hannover Medical School, Hannover, Germany., Jin R; Department of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, CA, USA., Rakoff-Nahoum S; Department of Microbiology, Harvard Medical School, Boston, MA, USA.; Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.; Division of Infectious Diseases, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Rao M; Division of Gastroenterology, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. meenakshi.rao@childrens.harvard.edu., Dong M; Department of Urology, Boston Children's Hospital, Boston, MA, USA. min.dong@childrens.harvard.edu.; Department of Surgery, Harvard Medical School, Boston, MA, USA. min.dong@childrens.harvard.edu.; Department of Microbiology, Harvard Medical School, Boston, MA, USA. min.dong@childrens.harvard.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Oct; Vol. 622 (7983), pp. 611-618. Date of Electronic Publication: 2023 Sep 12.
DOI: 10.1038/s41586-023-06607-2
Abstrakt: Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections 1,2 . The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization 3-6 , 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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