Outbreaks of Typhlocolitis Caused by Hypervirulent Group ST1 Clostridioides difficile in Highly Immunocompromised Strains of Mice

• Published in: Comparative medicine Vol. 70; no. 3; pp. 277 - 290
• Main Authors: Ma, Kathleen G L, Lertpiriyapong, Kvin, Piersigilli, Alessandra, Dobtsis, Irina, Wipf, Juliette R K, Littmann, Eric R, Leiner, Ingrid, Pamer, Eric G, Ricart Arbona, Rodolfo J, Lipman, Neil S
• Format: Journal Article
• Language: English
• Published: United States American Association for Laboratory Animal Science 01.06.2020
• Subjects: Amoxicillin - administration & dosage; Amoxicillin - adverse effects; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Case Studies; Clostridioides difficile - isolation & purification; Clostridium Infections - mortality; Clostridium Infections - veterinary; Diarrhea - etiology; Diarrhea - veterinary; Disease Outbreaks - veterinary; Immunocompromised Host; Mice; Mice, Inbred NOD
• ISSN: 1532-0820; 2769-819X
• DOI: 10.30802/AALAS-CM-19-000109

Clostridioides difficile is an enteric pathogen that can cause significant clinical disease in both humans and animals. However, clinical disease arises most commonly after treatment with broad-spectrum antibiotics. The organism's ability to cause naturally occurring disease in mice is rare, and little is known about its clinical significance in highly immunocompromised mice. We report on 2 outbreaks of diarrhea associated with C. difficile in mice. In outbreak 1, 182 of approximately 2, 400 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) and related strains of mice became clinically ill after cessation of a 14-d course of 0.12% amoxicillin feed to control an increase in clinical signs associated with Corynebacterium bovis infection. Most mice had been engrafted with human tumors; the remainder were experimentally naïve. Affected animals exhibited 1 of 3 clinical syndromes: 1) peracute death; 2) severe diarrhea leading to euthanasia or death; or 3) mild to moderate diarrhea followed by recovery. A given cage could contain both affected and unaffected mice. Outbreak 2 involved a small breeding colony (approximately 50 mice) of NOD. CB17-Prkdcscid/NCrCrl (NOD-scid) mice that had not received antibiotics or experimental manipulations. In both outbreaks, C. difficile was isolated, and toxins A and B were detected in intestinal content or feces. Histopathologic lesions highly suggestive of C. difficile enterotoxemia included fibrinonecrotizing and neutrophilic typhlocolitis with characteristic 'volcano' erosions or pseudomembrane formation. Genomic analysis of 4 isolates (3 from outbreak 1 and 1 from outbreak 2) revealed that these isolates were closely related to a pathogenic human isolate, CD 196. To our knowledge, this report is the first to describe naturally occurring outbreaks of C. difficile-associated typhlocolitis with significant morbidity and mortality in highly immunocompromised strains of mice.