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Characterization of SlyA in Shigella flexneri Identifies a Novel Role in Virulence.

ABSTRACT: The SlyA transcriptional regulator has important roles in the virulence and pathogenesis of several members of the Enterobacteriaceae family, including Salmonella enterica serovar Typhimurium and Escherichia coli. Despite the identification of the slyA gene in Shigella flexneri nearly 2 decades ago, as well as the significant conservation of SlyA among enteric bacteria, the role of SlyA in Shigella remains unknown. The genes regulated by SlyA in closely related organisms often are absent from or mutated inS. flexneri, and consequently many described SlyA-dependent phenotypes are not present. By characterizing the expression of slyA and determining its ultimate effect in this highly virulent organism, we postulated that novel SlyA-regulated virulence phenotypes would be identified. In this study, we report the first analysis of SlyA in Shigella and show that (i) the slyA gene is transcribed and ultimately translated into protein, (ii) slyA promoter activity is maximal during stationary phase and is negatively autoregulated and positively regulated by the PhoP response regulator, (iii) the exogenous expression of slyA rescues transcription and virulence-associated deficiencies during virulence-repressed conditions, and (iv) the absence of slyA significantly decreases acid resistance, demonstrating a novel and important role in Shigella virulence. Cumulatively, our study illustrates unexpected parallels between the less conserved S. flexneri and S Typhimurium slyA promoters as well as a unique role for SlyA in Shigella virulence that has not been described previously in any closely related organism.

SUBMITTER: Weatherspoon-Griffin N

PROVIDER: S-EPMC4807491 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Characterization of SlyA in Shigella flexneri Identifies a Novel Role in Virulence.

Weatherspoon-Griffin Natasha N Wing Helen J HJ

Infection and immunity 20160324 4

The SlyA transcriptional regulator has important roles in the virulence and pathogenesis of several members of the Enterobacteriaceae family, including Salmonella enterica serovar Typhimurium and Escherichia coli. Despite the identification of the slyA gene in Shigella flexneri nearly 2 decades ago, as well as the significant conservation of SlyA among enteric bacteria, the role of SlyA in Shigella remains unknown. The genes regulated by SlyA in closely related organisms often are absent from or ...[more]

PMID: 26831468

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Project description:Shigella flexneri is an intracellular human pathogen that invades colonic cells and causes bloody diarrhea. S. flexneri evolved from commensal Escherichia coli, and genome comparisons reveal that S. flexneri has lost approximately 20% of its genes through the process of pathoadaptation, including a disproportionate number of genes associated with the turnover of the nucleotide-based second messenger cyclic di-GMP (c-di-GMP); however, the remaining c-di-GMP turnover enzymes are highly conserved. c-di-GMP regulates many behavioral changes in other bacteria in response to changing environmental conditions, including biofilm formation, but this signaling system has not been examined in S. flexneri. In this study, we expressed VCA0956, a constitutively active c-di-GMP synthesizing diguanylate cyclase (DGC) from Vibrio cholerae, in S. flexneri to determine if virulence phenotypes were regulated by c-di-GMP. We found that expressing VCA0956 in S. flexneri increased c-di-GMP levels, and this corresponds with increased biofilm formation and reduced acid resistance, host cell invasion, and plaque size. We examined the impact of VCA0956 expression on the S. flexneri transcriptome and found that genes related to acid resistance were repressed, and this corresponded with decreased survival to acid shock. We also found that individual S. flexneri DGC mutants exhibit reduced biofilm formation and reduced host cell invasion and plaque size, as well as increased resistance to acid shock. This study highlights the importance of c-di-GMP signaling in regulating S. flexneri virulence phenotypes. IMPORTANCE The intracellular human pathogen Shigella causes dysentery, resulting in as many as one million deaths per year. Currently, there is no approved vaccine for the prevention of shigellosis, and the incidence of antimicrobial resistance among Shigella species is on the rise. Here, we explored how the widely conserved c-di-GMP bacterial signaling system alters Shigella behaviors associated with pathogenesis. We found that expressing or removing enzymes associated with c-di-GMP synthesis results in changes in Shigella's ability to form biofilms, invade host cells, form lesions in host cell monolayers, and resist acid stress.

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Characterization of SlyA in Shigella flexneri Identifies a Novel Role in Virulence.

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Characterization of SlyA in Shigella flexneri Identifies a Novel Role in Virulence.

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