An Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection

ABSTRACT Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epi...

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Autores principales:	Carole J. Kuehl, Jonathan D. D’Gama, Alyson R. Warr, Matthew K. Waldor
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Shigella animal models bacillary dysentery host-pathogen interactions infant rabbit pathogenesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8151c03f2ad140418addf3933620eca0
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spelling	oai:doaj.org-article:8151c03f2ad140418addf3933620eca02021-11-15T15:56:57ZAn Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection10.1128/mBio.03105-192150-7511https://doaj.org/article/8151c03f2ad140418addf3933620eca02020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03105-19https://doaj.org/toc/2150-7511ABSTRACT Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that orogastric inoculation of infant rabbits with Shigella flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell to cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro. Expression of the proinflammatory chemokine interleukin 8 (IL-8), detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics. IMPORTANCE Shigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that orogastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization, and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.Carole J. KuehlJonathan D. D’GamaAlyson R. WarrMatthew K. WaldorAmerican Society for MicrobiologyarticleShigellaanimal modelsbacillary dysenteryhost-pathogen interactionsinfant rabbitpathogenesisMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Shigella animal models bacillary dysentery host-pathogen interactions infant rabbit pathogenesis Microbiology QR1-502
spellingShingle	Shigella animal models bacillary dysentery host-pathogen interactions infant rabbit pathogenesis Microbiology QR1-502 Carole J. Kuehl Jonathan D. D’Gama Alyson R. Warr Matthew K. Waldor An Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection
description	ABSTRACT Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that orogastric inoculation of infant rabbits with Shigella flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell to cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro. Expression of the proinflammatory chemokine interleukin 8 (IL-8), detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics. IMPORTANCE Shigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that orogastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization, and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.
format	article
author	Carole J. Kuehl Jonathan D. D’Gama Alyson R. Warr Matthew K. Waldor
author_facet	Carole J. Kuehl Jonathan D. D’Gama Alyson R. Warr Matthew K. Waldor
author_sort	Carole J. Kuehl
title	An Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection
title_short	An Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection
title_full	An Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection
title_fullStr	An Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection
title_full_unstemmed	An Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection
title_sort	oral inoculation infant rabbit model for <italic toggle="yes">shigella</italic> infection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/8151c03f2ad140418addf3933620eca0
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An Oral Inoculation Infant Rabbit Model for <italic toggle="yes">Shigella</italic> Infection

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