Kwang-Il Jeong1, Quanshun Zhang, John Nunnari, Saul Tzipori. 1. Division of Infectious Diseases, Department of Biomedical Sciences, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.
Abstract
BACKGROUND: The lack of a standardized laboratory animal model that mimics key aspects of human shigellosis remains a major obstacle to addressing questions about pathogenesis, screening therapeutics, and evaluation of vaccines. METHODS: We characterized a piglet model for Shigella dysenteriae type 1. RESULTS: Piglets developed acute diarrhea, anorexia, and dehydration, which could often be fatal, with symptom severity depending on age and dose. Bacteria were apparent in the lumen and on the surface epithelium throughout the gut initially, but severe mucosal damage and bacterial cellular invasion were most profound in the colon. Detached necrotic colonocytes were present in the lumen, with inflammatory cells outpouring from damaged mucosa. High levels of interleukin (IL)-8 and IL-12 were followed by high levels of other proinflammatory cytokines. Elevated levels of tumor necrosis factor-alpha, IL-1beta, IL-6, and IL-10 were detected in feces and in gut segments from infected animals. Bacteria were present inside epithelial cells and within colonic lamina propria. In contrast, an isogenic strain lacking Shiga toxin induced similar but milder symptoms, with moderate mucosal damage and lower cytokine levels. CONCLUSION: We conclude that piglets are highly susceptible to shigellosis, providing a useful tool with which to compare vaccine candidates for immunogenicity, reactogenicity, and response to challenge; investigate the role of virulence factors; and test the efficacy of microbial agents.
BACKGROUND: The lack of a standardized laboratory animal model that mimics key aspects of humanshigellosis remains a major obstacle to addressing questions about pathogenesis, screening therapeutics, and evaluation of vaccines. METHODS: We characterized a piglet model for Shigella dysenteriae type 1. RESULTS: Piglets developed acute diarrhea, anorexia, and dehydration, which could often be fatal, with symptom severity depending on age and dose. Bacteria were apparent in the lumen and on the surface epithelium throughout the gut initially, but severe mucosal damage and bacterial cellular invasion were most profound in the colon. Detached necrotic colonocytes were present in the lumen, with inflammatory cells outpouring from damaged mucosa. High levels of interleukin (IL)-8 and IL-12 were followed by high levels of other proinflammatory cytokines. Elevated levels of tumor necrosis factor-alpha, IL-1beta, IL-6, and IL-10 were detected in feces and in gut segments from infected animals. Bacteria were present inside epithelial cells and within colonic lamina propria. In contrast, an isogenic strain lacking Shiga toxin induced similar but milder symptoms, with moderate mucosal damage and lower cytokine levels. CONCLUSION: We conclude that piglets are highly susceptible to shigellosis, providing a useful tool with which to compare vaccine candidates for immunogenicity, reactogenicity, and response to challenge; investigate the role of virulence factors; and test the efficacy of microbial agents.
Authors: Rembert Pieper; Quanshun Zhang; Prashanth P Parmar; Shih-Ting Huang; David J Clark; Hamid Alami; Arthur Donohue-Rolfe; Robert D Fleischmann; Scott N Peterson; Saul Tzipori Journal: Proteomics Date: 2009-11 Impact factor: 3.984
Authors: Benjamin J Koestler; Cara M Ward; C R Fisher; Anubama Rajan; Anthony W Maresso; Shelley M Payne Journal: Infect Immun Date: 2019-03-25 Impact factor: 3.441
Authors: Srilatha Kuntumalla; Quanshun Zhang; John C Braisted; Robert D Fleischmann; Scott N Peterson; Arthur Donohue-Rolfe; Saul Tzipori; Rembert Pieper Journal: BMC Microbiol Date: 2011-06-24 Impact factor: 3.605
Authors: Run Shi; Xia Yang; Lu Chen; Hong-tao Chang; Hong-ying Liu; Jun Zhao; Xin-wei Wang; Chuan-qing Wang Journal: PLoS One Date: 2014-06-20 Impact factor: 3.240