Therapeutic Mechanism of Macrophage Inflammatory Protein 1 α Neutralizing Antibody (CCL3) in Clostridium difficile Infection in Mice.

Abstract

BACKGROUND:

Clostridium difficile infection (CDI) causes diarrhea and colitis. We aimed to find a common pathogenic pathway in CDI among humans and mice by comparing toxin-mediated effects in human and mouse colonic tissues.

METHOD:

Using multiplex enzyme-linked immunosorbent assay, we determined the cytokine secretion of toxin A- and B-treated human and mouse colonic explants.

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 (MIP) 1α secretion in both human and mouse explants. Toxin A reduced the expression of chloride anion exchanger SLC26A3 expression in mouse colonic explants and human colonic epithelial cells. Patients with CDI had increased colonic MIP-1 α expression and reduced colonic SLC26A3 (solute carrier family 26, member 3) compared with controls. Anti-MIP-1 α neutralizing antibody prevented death, ameliorated colonic injury, reduced colonic interleukin 1β (IL-1β) messenger RNA expression, and restored colonic SLC26a3 expression in C. difficile-infected mice. The anti-MIP-1 α neutralizing antibody prevented CDI recurrence. SLC26a3 inhibition augmented colonic IL-1 β messenger RNA expression and abolished the protective effect of anti-MIP-1 α neutralizing antibody in mice with CDI.

CONCLUSION:

MIP-1 α is a common toxin A-dependent chemokine in human and mouse colon. MIP-1 α mediates detrimental effects by reducing SLC26a3 and enhancing IL-1 β expression in the colon.

• Authors: Jiani Wang, Christina Ortiz, Lindsey Fontenot, Riya Mukhopadhyay, Ying Xie, Xinhua Chen, Hanping Feng, Charalabos Pothoulakis, Hon Wai Koon
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 221 Issue 10 Pg. 1623-1635 (04 27 2020) ISSN: 1537-6613 [Electronic] United States
• PMID: 31793629 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Chemical References

• Antibodies, Neutralizing
• Bacterial Toxins
• Ccl3 protein, mouse
• Chemokine CCL3
• Chloride-Bicarbonate Antiporters
• Enterotoxins
• Interleukin-1beta
• Macrophage Inflammatory Proteins
• RNA, Messenger
• SLC26A3 protein, human
• Sulfate Transporters
• tcdA protein, Clostridium difficile

Topics

• Animals
• Antibodies, Neutralizing (immunology, therapeutic use)
• Bacterial Toxins (toxicity)
• Chemokine CCL3 (immunology)
• Chloride-Bicarbonate Antiporters (genetics, metabolism)
• Clostridioides difficile
• Clostridium Infections (therapy)
• Colon (drug effects, metabolism, microbiology)
• Down-Regulation
• Enterotoxins (toxicity)
• Gene Expression Regulation (drug effects)
• Humans
• Interleukin-1beta (genetics, metabolism)
• Macrophage Inflammatory Proteins (immunology)
• Mice
• RNA, Messenger (genetics, metabolism)
• Sulfate Transporters (genetics, metabolism)