The therapeutic mechanism macrophage inflammatory protein 1 alpha (MIP-1α/CCL3) neutralizing antibody in Clostridium difficile infection in mice.

BACKGROUND Clostridium difficile infection (CDI) causes diarrhea and colitis. We aimed at finding a common pathogenic pathway in CDI among humans and mice by comparing toxin-mediated effects in human and mouse colonic tissues. METHOD We determined the cytokine secretion of toxin A- and B-treated human and mouse colonic explants using multiplex ELISA. RESULTS Toxin A and toxin B exposure to fresh human and mouse colonic explants caused different patterns of cytokine secretion. Toxin A induced macrophage inflammatory protein 1 alpha (MIP-1α) secretion in both human and mouse explants. Toxin A reduced chloride anion exchanger SLC26A3 expression in mouse colonic explants and human colonic epithelial cells. C. difficile-infected patients had increased colonic MIP-1α expression and reduced colonic SLC26A3 expression compared to controls. Anti-MIP-1α neutralizing antibody prevented mortality, ameliorated colonic injury, reduced colonic IL-1beta mRNA expression, and restored colonic Slc26a3 expression in C. difficile-infected mice. The anti-MIP-1α neutralizing antibody prevented CDI recurrence. Slc26a3 inhibition augmented colonic IL-1β mRNA expression and abolished the protective effect of anti-MIP-1α neutralizing antibody in C. difficile-infected mice. CONCLUSION MIP-1α is a common toxin A-dependent chemokine in human and mouse colon. MIP-1α mediates detrimental effects by reducing Slc26a3 and enhancing IL-1β expression in the colon.

• Publication year

  2019

• Venue

  Journal of Infectious Diseases

• Publication date

  2019-12-03

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1093/infdis/jiz640PMID 31793629PMCID PMC7184920
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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