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A Tailored Multivariate Mixture Model for Detecting Proteins of Concordant Change Among Virulent Strains of Clostridium Perfringens.

ABSTRACT: Necrotic enteritis (NE) is a serious disease of poultry caused by the bacterium C. perfringens. To identify proteins of C. perfringens that confer virulence with respect to NE, the protein secretions of four NE disease-producing strains and one baseline non-disease-producing strain of C. perfringens were examined. The problem then becomes a clustering task, for the identification of two extreme groups of proteins that were produced at either concordantly higher or concordantly lower levels across all four disease-producing strains compared to the baseline, when most of the proteins do not exhibit significant change across all strains. However, the existence of some nuisance proteins of discordant change may severely distort any biologically meaningful cluster pattern. We develop a tailored multivariate clustering approach to robustly identify the proteins of concordant change. Using a three-component normal mixture model as the skeleton, our approach incorporates several constraints to account for biological expectations and data characteristics. More importantly, we adopt a sparse mean-shift parameterization in the reference distribution, coupled with a regularized estimation approach, to flexibly accommodate proteins of discordant change. We explore the connections and differences between our approach and other robust clustering methods, and resolve the issue of unbounded likelihood under an eigenvalue-ratio condition. Simulation studies demonstrate the superior performance of our method compared with a number of alternative approaches. Our protein analysis along with further biological investigations may shed light on the discovery of the complete set of virulence factors in NE.

SUBMITTER: Chen K

PROVIDER: S-EPMC6095199 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A Tailored Multivariate Mixture Model for Detecting Proteins of Concordant Change Among Virulent Strains of Clostridium Perfringens.

Chen Kun K Mishra Neha N Smyth Joan J Bar Haim H Schifano Elizabeth E Kuo Lynn L Chen Ming-Hui MH

Journal of the American Statistical Association 20180612 522

Necrotic enteritis (NE) is a serious disease of poultry caused by the bacterium C. perfringens. To identify proteins of C. perfringens that confer virulence with respect to NE, the protein secretions of four NE disease-producing strains and one baseline non-disease-producing strain of C. perfringens were examined. The problem then becomes a clustering task, for the identification of two extreme groups of proteins that were produced at either concordantly higher or concordant ...[more]

PMID: 30122795

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Project description:BACKGROUND: Clostridium perfringens is a Gram-positive anaerobic bacterium causing severe diseases such as gas gangrene and pseudomembranosus colitis, that are generally due to the secretion of powerful extracellular toxins. The expression of toxin genes is mainly regulated by VirR, the response regulator of a two-component system. Up to now few targets only are known for this regulator and mainly in one strain (Strain 13). Due to the high genomic and phenotypic variability in toxin production by different strains, the development of effective strategies to counteract C. perfringens infections requires methodologies to reconstruct the VirR regulon from genome sequences. RESULTS: We implemented a two step computational strategy allowing to consider available information concerning VirR binding sites in a few species to scan all genomes of the same species, assuming the VirR targets are at least partially conserved across these strains. Results obtained are in agreement with previous works where experimental validation of the promoters have been performed and showed the presence of a core and an accessory regulon of VirR in C. perfringens strains with three target genes also located on plasmids. Moreover, the type E strain JGS1987 has the largest predicted regulon with as many as 10 VirR targets not found in the other genomes. CONCLUSIONS: In this work we exploited available experimental information concerning the targets of the VirR toxin regulator in one C. perfringens strain to obtain plausible predictions concerning target genes in genomes and plasmids of nearby strains. Our predictions are available for wet-lab researchers working on less characterized C. perfringens strains that can thus design focused experiments reducing the search space of their experiments and increasing the probability of characterizing positive targets with less efforts. Main result was that the VirR regulon is variable in different C. perfringens strains with 4 genes controlled in all but one strains and most genes controlled in one or two strains only.

Project description:Clostridium perfringens is a gastrointestinal pathogen capable of causing disease in a variety of hosts. Necrotic enteritis in chickens is caused by C. perfringens strains that produce the pore-forming toxin NetB, the major virulence factor for this disease. Like many other C. perfringens toxins and antibiotic resistance genes, NetB is encoded on a conjugative plasmid. Conjugative transfer of the netB-containing plasmid pJIR3535 has been demonstrated in vitro with a netB-null mutant. This study has investigated the effect of plasmid transfer on disease pathogenesis, with two genetically distinct transconjugants constructed under in vitro conditions, within the intestinal tract of chickens. This study also demonstrates that plasmid transfer can occur naturally in the host gut environment without the need for antibiotic selective pressure to be applied. The demonstration of plasmid transfer within the chicken host may have implications for the progression and pathogenesis of C. perfringens-mediated disease. Such horizontal gene transfer events are likely to be common in the clostridia and may be a key factor in strain evolution, both within animals and in the wider environment.IMPORTANCE Clostridium perfringens is a major gastrointestinal pathogen of poultry. C. perfringens strains that express the NetB pore-forming toxin, which is encoded on a conjugative plasmid, cause necrotic enteritis. This study demonstrated that the conjugative transfer of the netB-containing plasmid to two different nonpathogenic strains converted them into disease-causing strains with disease-causing capability similar to that of the donor strain. Plasmid transfer of netB and antibiotic resistance was also demonstrated to occur within the gastrointestinal tract of chickens, with approximately 14% of the isolates recovered comprising three distinct, in vivo-derived, transconjugant types. The demonstration of in vivo plasmid transfer indicates the potential importance of strain plasticity and the contribution of plasmids to strain virulence.

Dataset Information

A Tailored Multivariate Mixture Model for Detecting Proteins of Concordant Change Among Virulent Strains of Clostridium Perfringens.

Publications

A Tailored Multivariate Mixture Model for Detecting Proteins of Concordant Change Among Virulent Strains of <i>Clostridium Perfringens</i>.

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