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In silico analysis of sequenced strains of Clostridium difficile reveals a related set of conjugative transposons carrying a variety of accessory genes.

ABSTRACT: The human gut pathogen Clostridium difficile contains many conjugative transposons that have an array of accessory genes. In the current study, recently sequenced genomes were analyzed to identify new putative conjugative transposons. Eleven new elements in 5 C. difficile strains were identified and all had a similar structure to the previously described elements CTn1, CTn5 and CTn7 in C. difficile strain 630. Each element identified did however contain a new set of accessory genes compared with those previously reported; including those predicted to encode ABC transporters, a toxin/antitoxin system and multiple antibiotic resistance genes.

SUBMITTER: Brouwer MS

PROVIDER: S-EPMC3383454 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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In silico analysis of sequenced strains of Clostridium difficile reveals a related set of conjugative transposons carrying a variety of accessory genes.

Brouwer Michael S M MS Roberts Adam P AP Mullany Peter P Allan Elaine E

Mobile genetic elements 20120101 1

The human gut pathogen Clostridium difficile contains many conjugative transposons that have an array of accessory genes. In the current study, recently sequenced genomes were analyzed to identify new putative conjugative transposons. Eleven new elements in 5 C. difficile strains were identified and all had a similar structure to the previously described elements CTn1, CTn5 and CTn7 in C. difficile strain 630. Each element identified did however contain a new set of accessory genes compared with ...[more]

PMID: 22754747

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Project description: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.IMPORTANCEClostridium 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.

Project description:UNLABELLED:Clostridium difficile infection (CDI) is responsible for most of the definable cases of antibiotic- and hospital-associated diarrhea worldwide and is a frequent cause of morbidity and mortality in older patients. C. difficile, a multidrug-resistant anaerobic pathogen, causes disease by producing toxins A and B, which are controlled by an accessory gene regulator (Agr) quorum signaling system. Some C. difficile strains encode two Agr loci in their genomes, designated agr1 and agr2 The agr1 locus is present in all of the C. difficile strains sequenced to date, whereas the agr2 locus is present in a few strains. The functional roles of agr1 and agr2 in C. difficile toxin regulation and pathogenesis were unknown until now. Using allelic exchange, we deleted components of both agr loci and examined the mutants for toxin production and virulence. The results showed that the agr1 mutant cannot produce toxins A and B; toxin production can be restored by complementation with wild-type agr1 Furthermore, the agr1 mutant is able to colonize but unable to cause disease in a murine CDI model. These findings have profound implications for CDI treatment because we have uncovered a promising therapeutic target for the development of nonantibiotic drugs to treat this life-threatening emerging pathogen by targeting the toxins directly responsible for disease. IMPORTANCE:Within the last decade, the number of cases of C. difficile infections has been increasing exponentially in the United States, resulting in about 4.8 billion U.S. dollars in health care costs annually. As a multidrug-resistant, spore-forming, anaerobic pathogen, C. difficile overpopulates the colon after the gut microbiota has been altered by antibiotic therapy. With increasing resistance to antibiotic treatment of C. difficile infections, patients are experiencing higher costs of health care and a lower quality of life as treatment options decrease. During infection, C. difficile produces toxins A and B, which directly cause disease. As a result, the toxins have become promising nonantibiotic treatment targets. Here, we have identified a pathway responsible for activating the production of the toxins. This important finding opens up a unique therapeutic target for the development of a novel nonantibiotic therapy for C. difficile infections.

Dataset Information

In silico analysis of sequenced strains of Clostridium difficile reveals a related set of conjugative transposons carrying a variety of accessory genes.

Publications

In silico analysis of sequenced strains of Clostridium difficile reveals a related set of conjugative transposons carrying a variety of accessory genes.

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