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Role of the virulence plasmid in acid resistance of Shigella flexneri.

ABSTRACT: Virulence plasmid (VP) acquisition was a key step in the evolution of Shigella from a non-pathogenic Escherichia coli ancestor to a pathogenic genus. In addition, the co-evolution and co-ordination of chromosomes and VPs was also a very important step in the evolutionary process. To investigate the cross-talk between VPs and bacterial chromosomes, we analyzed the expression profiles of protein complexes and protein monomers in three wild-type Shigella flexneri strains and their corresponding VP deletion mutants. A non-pathogenic wild-type E. coli strain and mutant E. coli strains harboring three Shigella VPs were also analyzed. Comparisons showed that the expression of chromosome-encoded proteins GadA/B and AtpA/D, which are associated with intracellular proton flow and pH tuning of bacterial cells, was significantly altered following acquisition or deletion of the VP. The acid tolerance of the above strains was also compared, and the results confirmed that the presence of the VP reduced the bacterial survival rate in extremely acidic environments, such as that in the host stomach. These results further our understanding of the evolution from non-pathogenic E. coli to Shigella, and highlight the importance of co-ordination between heterologous genes and the host chromosome in the evolution of bacterial species.

SUBMITTER: Niu C

PROVIDER: S-EPMC5404508 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Role of the virulence plasmid in acid resistance of Shigella flexneri.

Niu Chang C Yang Jing J Liu Hongsheng H Cui Yong Y Xu Huijie H Wang Ruifeng R Liu Xiankai X Feng Erling E Wang Dongshu D Pan Chao C Xiao Wei W Liu Xiaoqing X Zhu Li L Wang Hengliang H

Scientific reports 20170425

Virulence plasmid (VP) acquisition was a key step in the evolution of Shigella from a non-pathogenic Escherichia coli ancestor to a pathogenic genus. In addition, the co-evolution and co-ordination of chromosomes and VPs was also a very important step in the evolutionary process. To investigate the cross-talk between VPs and bacterial chromosomes, we analyzed the expression profiles of protein complexes and protein monomers in three wild-type Shigella flexneri strains and their corresponding VP ...[more]

PMID: 28440329

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Project description:Non-human primates (NHPs) for biomedical research are commonly infected with Shigella spp. that can cause acute dysentery or chronic episodic diarrhea. These animals are often prophylactically and clinically treated with quinolone antibiotics to eradicate these possible infections. However, chromosomally- and plasmid-mediated antibiotic resistance has become an emerging concern for species in the family Enterobacteriaceae. In this study, five individual isolates of multi-drug resistant Shigella flexneri were isolated from the feces of three macaques. Antibiotic susceptibility testing confirmed resistance or decreased susceptibility to ampicillin, amoxicillin-clavulanic acid, cephalosporins, gentamicin, tetracycline, ciprofloxacin, enrofloxacin, levofloxacin, and nalidixic acid. S. flexneri isolates were susceptible to trimethoprim-sulfamethoxazole, and this drug was used to eradicate infection in two of the macaques. Plasmid DNA from all isolates was positive for the plasmid-encoded quinolone resistance gene qnrS, but not qnrA and qnrB. Conjugation and transformation of plasmid DNA from several S. flexneri isolates into antibiotic-susceptible Escherichia coli strains conferred the recipients with resistance or decreased susceptibility to quinolones and beta-lactams. Genome sequencing of two representative S. flexneri isolates identified the qnrS gene on a plasmid-like contig. These contigs showed >99% homology to plasmid sequences previously characterized from quinolone-resistant Shigella flexneri 2a and Salmonella enterica strains. Other antibiotic resistance genes and virulence factor genes were also identified in chromosome and plasmid sequences in these genomes. The findings from this study indicate macaques harbor pathogenic S. flexneri strains with chromosomally- and plasmid-encoded antibiotic resistance genes. To our knowledge, this is the first report of plasmid-mediated quinolone resistance in S. flexneri isolated from NHPs and warrants isolation and antibiotic testing of enteric pathogens before treating macaques with quinolones prophylactically or therapeutically.

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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Role of the virulence plasmid in acid resistance of Shigella flexneri.

Publications

Role of the virulence plasmid in acid resistance of Shigella flexneri.

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