Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence

ABSTRACT Clostridium difficile is a spore-forming anaerobic bacterium that causes colitis in patients with disrupted colonic microbiota. While some individuals are asymptomatic C. difficile carriers, symptomatic disease ranges from mild diarrhea to potentially lethal toxic megacolon. The wide diseas...

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Autores principales:	Brittany B. Lewis, Rebecca A. Carter, Lilan Ling, Ingrid Leiner, Ying Taur, Mini Kamboj, Erik R. Dubberke, Joao Xavier, Eric G. Pamer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Clostridium difficile accessory genome bile salt genome analysis pathogenicity locus toxin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9c54828146554dea95310db8ae19f8c7
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spelling	oai:doaj.org-article:9c54828146554dea95310db8ae19f8c72021-11-15T15:51:43ZPathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence10.1128/mBio.00885-172150-7511https://doaj.org/article/9c54828146554dea95310db8ae19f8c72017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00885-17https://doaj.org/toc/2150-7511ABSTRACT Clostridium difficile is a spore-forming anaerobic bacterium that causes colitis in patients with disrupted colonic microbiota. While some individuals are asymptomatic C. difficile carriers, symptomatic disease ranges from mild diarrhea to potentially lethal toxic megacolon. The wide disease spectrum has been attributed to the infected host’s age, underlying diseases, immune status, and microbiome composition. However, strain-specific differences in C. difficile virulence have also been implicated in determining colitis severity. Because patients infected with C. difficile are unique in terms of medical history, microbiome composition, and immune competence, determining the relative contribution of C. difficile virulence to disease severity has been challenging, and conclusions regarding the virulence of specific strains have been inconsistent. To address this, we used a mouse model to test 33 clinical C. difficile strains isolated from patients with disease severities ranging from asymptomatic carriage to severe colitis, and we determined their relative in vivo virulence in genetically identical, antibiotic-pretreated mice. We found that murine infections with C. difficile clade 2 strains (including multilocus sequence type 1/ribotype 027) were associated with higher lethality and that C. difficile strains associated with greater human disease severity caused more severe disease in mice. While toxin production was not strongly correlated with in vivo colonic pathology, the ability of C. difficile strains to grow in the presence of secondary bile acids was associated with greater disease severity. Whole-genome sequencing and identification of core and accessory genes identified a subset of accessory genes that distinguish high-virulence from lower-virulence C. difficile strains. IMPORTANCE Clostridium difficile is an important cause of hospital-associated intestinal infections, and recent years have seen an increase in the number and severity of cases in the United States. A patient’s antibiotic history, immune status, and medical comorbidities determine, in part, the severity of C. difficile infection. The relative virulence of different clinical C. difficile strains, although postulated to determine disease severity in patients, has been more difficult to consistently associate with mild versus severe colitis. We tested 33 distinct clinical C. difficile isolates for their ability to cause disease in genetically identical mice and found that C. difficile strains belonging to clade 2 were associated with higher mortality. Differences in survival were not attributed to differences in toxin production but likely resulted from the distinct gene content in the various clinical isolates.Brittany B. LewisRebecca A. CarterLilan LingIngrid LeinerYing TaurMini KambojErik R. DubberkeJoao XavierEric G. PamerAmerican Society for MicrobiologyarticleClostridium difficileaccessory genomebile saltgenome analysispathogenicity locustoxinMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium difficile accessory genome bile salt genome analysis pathogenicity locus toxin Microbiology QR1-502
spellingShingle	Clostridium difficile accessory genome bile salt genome analysis pathogenicity locus toxin Microbiology QR1-502 Brittany B. Lewis Rebecca A. Carter Lilan Ling Ingrid Leiner Ying Taur Mini Kamboj Erik R. Dubberke Joao Xavier Eric G. Pamer Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence
description	ABSTRACT Clostridium difficile is a spore-forming anaerobic bacterium that causes colitis in patients with disrupted colonic microbiota. While some individuals are asymptomatic C. difficile carriers, symptomatic disease ranges from mild diarrhea to potentially lethal toxic megacolon. The wide disease spectrum has been attributed to the infected host’s age, underlying diseases, immune status, and microbiome composition. However, strain-specific differences in C. difficile virulence have also been implicated in determining colitis severity. Because patients infected with C. difficile are unique in terms of medical history, microbiome composition, and immune competence, determining the relative contribution of C. difficile virulence to disease severity has been challenging, and conclusions regarding the virulence of specific strains have been inconsistent. To address this, we used a mouse model to test 33 clinical C. difficile strains isolated from patients with disease severities ranging from asymptomatic carriage to severe colitis, and we determined their relative in vivo virulence in genetically identical, antibiotic-pretreated mice. We found that murine infections with C. difficile clade 2 strains (including multilocus sequence type 1/ribotype 027) were associated with higher lethality and that C. difficile strains associated with greater human disease severity caused more severe disease in mice. While toxin production was not strongly correlated with in vivo colonic pathology, the ability of C. difficile strains to grow in the presence of secondary bile acids was associated with greater disease severity. Whole-genome sequencing and identification of core and accessory genes identified a subset of accessory genes that distinguish high-virulence from lower-virulence C. difficile strains. IMPORTANCE Clostridium difficile is an important cause of hospital-associated intestinal infections, and recent years have seen an increase in the number and severity of cases in the United States. A patient’s antibiotic history, immune status, and medical comorbidities determine, in part, the severity of C. difficile infection. The relative virulence of different clinical C. difficile strains, although postulated to determine disease severity in patients, has been more difficult to consistently associate with mild versus severe colitis. We tested 33 distinct clinical C. difficile isolates for their ability to cause disease in genetically identical mice and found that C. difficile strains belonging to clade 2 were associated with higher mortality. Differences in survival were not attributed to differences in toxin production but likely resulted from the distinct gene content in the various clinical isolates.
format	article
author	Brittany B. Lewis Rebecca A. Carter Lilan Ling Ingrid Leiner Ying Taur Mini Kamboj Erik R. Dubberke Joao Xavier Eric G. Pamer
author_facet	Brittany B. Lewis Rebecca A. Carter Lilan Ling Ingrid Leiner Ying Taur Mini Kamboj Erik R. Dubberke Joao Xavier Eric G. Pamer
author_sort	Brittany B. Lewis
title	Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence
title_short	Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence
title_full	Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence
title_fullStr	Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence
title_full_unstemmed	Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence
title_sort	pathogenicity locus, core genome, and accessory gene contributions to <italic toggle="yes">clostridium difficile</italic> virulence
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/9c54828146554dea95310db8ae19f8c7
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Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to <italic toggle="yes">Clostridium difficile</italic> Virulence

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