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Clostridium difficile extracytoplasmic function ? factor ?V regulates lysozyme resistance and is necessary for pathogenesis in the hamster model of infection.

ABSTRACT: Clostridium difficile is a clinically important pathogen and the most common cause of hospital-acquired infectious diarrhea. Expression of the C. difficile gene csfV, which encodes ?(V), an extracytoplasmic function ? factor, is induced by lysozyme, which damages the peptidoglycan of bacteria. Here we show that ?(V) is required for lysozyme resistance in C. difficile. Using microarray analysis, we identified the C. difficile genes whose expression is dependent upon ?(V) and is induced by lysozyme. Although the peptidoglycan of wild-type C. difficile is intrinsically highly deacetylated, we have found that exposure to lysozyme leads to additional peptidoglycan deacetylation. This lysozyme-induced deacetylation is dependent upon ?(V). Expression of pdaV, which encodes a putative peptidoglycan deacetylase, was able to increase lysozyme resistance of a csfV mutant. The csfV mutant strain is severely attenuated compared to wild-type C. difficile in a hamster model of C. difficile-associated disease. We conclude that the ?(V) signal transduction system, which senses the host innate immune defense enzyme lysozyme, is required for lysozyme resistance and is necessary during C. difficile infection.

SUBMITTER: Ho TD

PROVIDER: S-EPMC4019185 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Clostridium difficile extracytoplasmic function σ factor σV regulates lysozyme resistance and is necessary for pathogenesis in the hamster model of infection.

Ho Theresa D TD Williams Kyle B KB Chen Yan Y Helm Richard F RF Popham David L DL Ellermeier Craig D CD

Infection and immunity 20140324 6

Clostridium difficile is a clinically important pathogen and the most common cause of hospital-acquired infectious diarrhea. Expression of the C. difficile gene csfV, which encodes σ(V), an extracytoplasmic function σ factor, is induced by lysozyme, which damages the peptidoglycan of bacteria. Here we show that σ(V) is required for lysozyme resistance in C. difficile. Using microarray analysis, we identified the C. difficile genes whose expression is dependent upon σ(V) and is induced by lysozym ...[more]

PMID: 24664503

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Project description:The intracellular signaling molecule cyclic diguanylate (c-di-GMP) regulates many processes in bacteria, with a central role in controlling the switch between motile and nonmotile lifestyles. Recent work has shown that in Clostridium difficile (also called Clostridioides difficile), c-di-GMP regulates swimming and surface motility, biofilm formation, toxin production, and intestinal colonization. In this study, we determined the transcriptional regulon of c-di-GMP in C. difficile, employing overexpression of a diguanylate cyclase gene to artificially manipulate intracellular c-di-GMP. Consistent with prior work, c-di-GMP regulated the expression of genes involved in swimming and surface motility. c-di-GMP also affected the expression of multiple genes encoding cell envelope proteins, several of which affected biofilm formation in vitro A substantial proportion of the c-di-GMP regulon appears to be controlled either directly or indirectly via riboswitches. We confirmed the functionality of 11 c-di-GMP riboswitches, demonstrating their effects on downstream gene expression independent of the upstream promoters. The class I riboswitches uniformly functioned as "off" switches in response to c-di-GMP, while class II riboswitches acted as "on" switches. Transcriptional analyses of genes 3' of c-di-GMP riboswitches over a broad range of c-di-GMP levels showed that relatively modest changes in c-di-GMP levels are capable of altering gene transcription, with concomitant effects on microbial behavior. This work expands the known c-di-GMP signaling network in C. difficile and emphasizes the role of the riboswitches in controlling known and putative virulence factors in C. difficile IMPORTANCE In Clostridium difficile, the signaling molecule c-di-GMP regulates multiple processes affecting its ability to cause disease, including swimming and surface motility, biofilm formation, toxin production, and intestinal colonization. In this study, we used RNA-seq to define the transcriptional regulon of c-di-GMP in C. difficile Many new targets of c-di-GMP regulation were identified, including multiple putative colonization factors. Transcriptional analyses revealed a prominent role for riboswitches in c-di-GMP signaling. Only a subset of the 16 previously predicted c-di-GMP riboswitches were functional in vivo and displayed potential variability in their response kinetics to c-di-GMP. This work underscores the importance of studying c-di-GMP riboswitches in a relevant biological context and highlights the role of the riboswitches in controlling gene expression in C. difficile.

Dataset Information

Clostridium difficile extracytoplasmic function ? factor ?V regulates lysozyme resistance and is necessary for pathogenesis in the hamster model of infection.

Publications

Clostridium difficile extracytoplasmic function σ factor σV regulates lysozyme resistance and is necessary for pathogenesis in the hamster model of infection.

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