Virulence and mutation rates of Salmonella typhimurium strains with increased mutagenic strength in a mouse model

Campoy, Susana

doi:10.1016/s0378-1097(00)00192-0

Cited by 5 publications

(7 citation statements)

References 19 publications

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“…1). These results are consistent with recent studies, which showed that inactivation of mutS or mutL in S. enterica did not increase virulence as evaluated by the amount of inoculum required to kill 50% of infected mice (4,10,32) or the time until the death of the animal (32). However, mutator strains may have an indirect advantage in the presence of antibiotics since it has been shown that the course of infections caused by the mutator strains is unaffected by the presence of a quinolone, whereas with the wild-type strain, antibiotic treatment extends the survival of the mice (D. S. Thaler, personal communication).…”

Section: Discussionsupporting

confidence: 93%

Mutator Natural Escherichia coli Isolates Have an Unusual Virulence Phenotype

Picard¹,

Duriez

Gouriou³

et al. 2001

Infect Immun

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A small percentage of natural Escherichia coli isolates (both commensal and pathogenic) have a mutator phenotype related to defects in methyl-directed mismatch repair (MR) genes. We investigated whether there was a direct link between the mutator phenotype and virulence by (i) studying the relationships between mutation rate and virulence in a mouse model of extraintestinal virulence for 88 commensal and extraintestinal pathogenic E. coli isolates and (ii) comparing the virulence in mice of MR-deficient and MR-proficient strains that were otherwise isogenic. The results provide no support for the hypothesis that the mutator phenotype has a direct role in virulence or is associated with increased virulence. Most of the natural mutator strains studied displayed an unusual virulence phenotype with (i) a lack of correspondence between the number of virulence determinants and pathogenicity in mice and (ii) an intermediate level of virulence. On a large evolutionary scale, the mutator phenotype may help parasites to achieve an intermediate rate of virulence which mathematical models predict to be selected for during long-term parasite-host interactions.Natural bacterial isolates of Escherichia coli and Salmonella enterica have recently been shown to have highly variable mutation rates (15,18). A small percentage of the natural strains studied were strong mutators (i.e., they have a frequency of mutation 50 to 100 times higher than that of the remaining strains). Most of these strong mutator strains are defective in the methyl-directed mismatch repair (MR) genes (mutS, mutL, mutH, and mutU). The MR system increases the fidelity of replication by correcting DNA biosynthetic errors such as base mismatches and insertion-deletions of up to four bases and inhibits recombination between nonidentical DNA sequences (27).One of the main issues raised by these data is the possibility that greater genetic variability is associated with pathogenesis. Indeed, the mutator phenotype may enable bacteria to adapt to new niches and to escape immune surveillance by generating numerous mutations (20,21). In addition, if the mutator phenotype is related to inactivation of the MR system, it may enable bacteria to acquire additional elements such as pathogenicity islands more easily by horizontal transfer (23). MRdefective strains have been identified among commensal and pathogenic (intestinal and extraintestinal) strains (15, 18), but (i) the numbers of strains studied are too small to demonstrate a significantly higher frequency of mutators in pathogenic isolates and (ii) it is difficult to distinguish between commensal and pathogenic strains because enteric E. coli isolated in commensal situations may be the natural reservoir of pathogenic strains (6). Thus, further studies are clearly needed to determine the specific role, if any, of the mutator phenotype in E. coli pathogenesis (30).In the present study we used two approaches to explore the possible link between mutator phenotype and virulence. First, we studied the relationships betwee...

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Section: Discussionsupporting

confidence: 93%

Mutator Natural Escherichia coli Isolates Have an Unusual Virulence Phenotype

Picard¹,

Duriez

Gouriou³

et al. 2001

Infect Immun

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“…The virulence characterization of 12-23c verified (4,27) that MMR is dispensable for Salmonella virulence, despite the contribution of MMR to the virulence of other intracellular pathogens (18). Nevertheless, DNA damage does occur during the course of Salmonella infection.…”

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confidence: 88%

“…While the Rep Ϫ mutants were all severely attenuated in mice and Sif negative (Sif Ϫ ), the Sif Ϫ phenotype was found to be unlinked to the MudJ insertional mutations (24). To gain insight into the molecular basis for the Rep Ϫ phenotype and possible causes for the unlinked Sif Ϫ phenotype, we genetically characterized the three Rep Ϫ mutants identified by [3][4][5][6][7][8][9][10][11][17][18][19][20][21]. Strain 12-23 was originally found to be a rough lipopolysaccharide (LPS) variant refractile to P22 transduction (15).…”

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confidence: 99%

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Molecular Characterization of the Prototrophic Salmonella Mutants Defective for Intraepithelial Replication

Suvarnapunya

Zurawski²,

Guy

et al. 2003

Infect Immun

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Three MudJ prototrophs demonstrated that intracellular replication is a Salmonella virulence trait (K. Y. Leung and B. B. Finlay, Proc. Natl. Acad. Sci. USA, 88:11470-11474, 1991). mutS and mutH are disrupted in mutants 3-11 and 12-23, and ssaQ is disrupted in mutant 17-21. Further analysis revealed that loss of Salmonella pathogenicity island 2 function underlies the intracellular replication defect of 3-11 and 17-21

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“…This possibility is unlikely, since it has been widely described that there is no decrease in the virulence of S. enterica hypermutable phenotypes (5,26).…”

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confidence: 97%

Relevance of DNA Alkylation Damage Repair Systems in Salmonella enterica Virulence

et al. 2010

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Systematic inactivation of pathways involved in DNA alkylation damage repair demonstrated that inactivation of the ada, ogt, tag, uvrA, and mfd genes is required to detect a Salmonella enterica virulence decrease. Furthermore, the fitness of S. enterica, defective in these genes, is lowered only when the bacterium is orally, but not intraperitoneally, inoculated.Bacteria are exposed to a wide variety of DNA-injuring agents, including alkylating agents, and their effects have been well studied (12,17,18). The repair of alkylated DNA in bacterial cells has been described mainly in Escherichia coli (12,18), which presents the following two different mechanisms to eliminate alkyl radicals from its DNA: (i) the alkylinduced expression of genes encoding the necessary repair enzymes (12, 17) and (ii) the constitutive synthesis of such proteins (9).Many bacterial species have a genetic network, known as the adaptive response, which functions to repair alkyl lesions in the bacterial DNA (18,19) and is regulated by the Ada protein, which also possesses methyltransferase activity (18). Transfer of a methyl from DNA-methylated phosphates to the Cys-37 residue of Ada (17) triggers a conformational change in this protein that converts it into a positive transcriptional regulator. Once activated, Ada stimulates the expression of its own transcriptional unit, including the alkB gene, which encodes an N 1 -meA-DNA dioxygenase, and the alkA and aidB genes, which encode a N 3 -meA-DNA-glycosylase and a flavin-containing DNA binding protein, respectively (9).Bacteria also possess the following two additional enzymes involved in the repair of alkylated DNA: Ogt (O 6 -meG-DNA methyltransferase) and Tag (N 3 -meA-DNA glycosylase) (9). Expression of the ogt and tag genes is constitutive and does not depend on the presence of DNA alkylation (9). Despite the importance of alkylated DNA repair, there is very little information concerning the relevance of this process in pathogenic bacteria.To determine the implications of DNA alkylation damage repair in Salmonella enterica virulence, mutants defective in the ada gene, or genes under its control (alkA, alkB and aidB), or mutants defective in the ogt and tag genes were constructed using the one-step PCR-based gene replacement method (6).As expected, survival assays showed that each of these single mutants was more sensitive than the wild-type strain to several alkylating agents, including N-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG), methyl methanesulfonate (MMS), and diethyl sulfate (DES) (data not shown). Furthermore, competition assays between each of these mutants and the wild-type strain, carried out as reported previously (3, 4), demonstrated that the inactivation of neither ada, ogt, nor tag had any effect on the virulence of S. enterica cells, regardless of whether the bacteria were inoculated orally or intraperitoneally (i.p.) in BALB/c mice (data not shown).In light of these results, S. enterica strains carrying all possible double combinations of the ada, tag, and ogt mutations we...

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Virulence and mutation rates of Salmonella typhimurium strains with increased mutagenic strength in a mouse model

Cited by 5 publications

References 19 publications

Mutator Natural Escherichia coli Isolates Have an Unusual Virulence Phenotype

Mutator Natural Escherichia coli Isolates Have an Unusual Virulence Phenotype

Molecular Characterization of the Prototrophic Salmonella Mutants Defective for Intraepithelial Replication

Relevance of DNA Alkylation Damage Repair Systems in Salmonella enterica Virulence

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