Caenorhabditis elegans-Based Screen Identifies Salmonella Virulence Factors Required for Conserved Host-Pathogen Interactions

Tenor, Jennifer L.; McCormick, Beth A.; Ausubel, Frederick M.; Aballay, Alejandro

doi:10.1016/j.cub.2004.05.050

Cited by 133 publications

(149 citation statements)

References 34 publications

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“…1). As previously shown, the glp-4 (ts) strain responded to serovar Typhimurium infections similarly to the wild-type nematode strain N2 (28). The virulence of antibiotic-resistant strains was compared to the wild-type Salmonella sp.…”

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confidence: 92%

“…Some bacterial pathogens, such as Salmonella enterica serovar Typhimurium are able to establish a persistent infection in the intestine of C. elegans, reducing the life span of the host. Several genes needed for virulence in mammals are also required for pathogenesis in C. elegans (2,10,16,28), implying that the invasion and proliferation of serovar Typhimurium in the host intestine depend on mechanisms common to the nematode and mammals. This makes C. elegans a relevant model for determining the infectivity and fitness of antibiotic-resistant bacteria during a host infection.…”

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confidence: 99%

“…Although mouse models have been used for these purposes, simpler invertebrates such as Caenorhabditis elegans have recently become more attractive for assessing the in vivo biological costs of antibiotic resistance (23,24). Many bacterial genes known to be required for mammalian pathogenesis are needed also in the nematode (1,9,11,15,16,27,28). Some bacterial pathogens, such as Salmonella enterica serovar Typhimurium are able to establish a persistent infection in the intestine of C. elegans, reducing the life span of the host.…”

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confidence: 99%

“…Similarly, the PhoP/Q signal transduction system and several of the genes located in the pathogenicity island 1 are required for virulence in both mammals and C. elegans (2,10). The identification of virulence factors that are important in both mammals and C. elegans can conceivably be explained by conserved interactions with the innate immunity systems (28) and/or similarities in the actual growth environment (e.g., nutrient levels). Conversely, the lack of a correlation between mice and C. elegans can be explained by the absence of professional phagocytic cells and adaptive immune responses in C. elegans.…”

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confidence: 99%

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Caenorhabditis elegans as a Model To Determine Fitness of Antibiotic-Resistant Salmonella enterica Serovar Typhimurium

Paulander

Pennhag

Andersson

et al. 2007

Antimicrob Agents Chemother

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We used the ability of Salmonella enterica serovar Typhimurium to colonize the gut of Caenorhabditis elegans to measure the fitness costs imposed by antibiotic resistance mutations. The fitness costs determined in the nematode were similar to those measured in mice, validating its use as a simple host model to evaluate bacterial fitness.The persistence of antibiotic-resistant bacteria largely depends on the effect of the resistance mechanism on fitness (reviewed in references 3 and 4). The cost caused by resistance mutations can be decreased by second-site mutations that restore fitness without a loss of resistance (3,17,18). This process has been observed in many cases both in vitro (13,17,19,22,25) and in clinical settings (6,8,20,26). These findings suggest that antibiotic resistance may persist in the population for a long time and that the determination of fitness parameters is of great importance for predicting the risk of resistance development.Fitness costs are usually determined by comparing the growth rates of resistant and susceptible bacteria (3). Although mouse models have been used for these purposes, simpler invertebrates such as Caenorhabditis elegans have recently become more attractive for assessing the in vivo biological costs of antibiotic resistance (23, 24). Many bacterial genes known to be required for mammalian pathogenesis are needed also in the nematode (1,9,11,15,16,27,28). Some bacterial pathogens, such as Salmonella enterica serovar Typhimurium are able to establish a persistent infection in the intestine of C. elegans, reducing the life span of the host. Several genes needed for virulence in mammals are also required for pathogenesis in C. elegans (2,10,16,28), implying that the invasion and proliferation of serovar Typhimurium in the host intestine depend on mechanisms common to the nematode and mammals. This makes C. elegans a relevant model for determining the infectivity and fitness of antibiotic-resistant bacteria during a host infection.Virulence assays were performed as previously described (2) using C. elegans SS104 [glp-4 (ts)] (5), a temperature-sensitive mutant that produces progeny at 15°C but not at 25°C. At least 50 synchronized worms in larval stage L4 were transferred on solid nematode growth medium (NGM) (12) seeded with 10 l of serovar Typhimurium mixed 1:100 with the nonpathogenic Escherichia coli strain OP50 and maintained at 25°C. Both bacterial species grow on NGM agar with no mutual inhibition. The number of viable worms was monitored every day, and the percentages of nematode survival calculated by the KaplanMeier method (14) were used for plotting the percent survival as a function of time. Survival kinetics were compared by using the nonparametric log-rank test and were considered statistically different when P was Ͻ0.05. We found that the time to death for 50% of the nematodes was 9 days when fed with E. coli OP50 and 7 days after ingestion of the virulent wild-type strain LT2 of serovar Typhimurium (Fig. 1). As previously shown, the glp-4 (ts) strain resp...

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confidence: 92%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Caenorhabditis elegans as a Model To Determine Fitness of Antibiotic-Resistant Salmonella enterica Serovar Typhimurium

Paulander

Pennhag

Andersson

et al. 2007

Antimicrob Agents Chemother

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“…StpA, an H-NS paralogue, was found to repress ompS1 in an hns background; and LeuO, a LysR-type regulator, positively regulates ompS1 expression by antagonizing H-NS and StpA (De la Cruz et al, 2007). LeuO has been implicated in several functions, such as stress resistance, virulence and biofilm formation (VanBogelen et al, 1996;Fang et al, 2000;Majumder et al, 2001;Tenor et al, 2004; Lawley et al, 2006;Moorthy & Watnick, 2005;Rodríguez-Morales et al, 2006). Recently, our group has described several genes regulated by LeuO in S. Typhi (Hernández-Lucas et al, 2008).…”

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confidence: 99%

The DNA static curvature has a role in the regulation of the ompS1 porin gene in Salmonella enterica serovar Typhi

et al. 2009

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The DNA static curvature has been described to play a key role as a regulatory element in the transcription process of several bacterial genes. Here, the role of DNA curvature in the expression of the ompS1 porin gene in Salmonella enterica serovar Typhi is described. The web server MUTACURVE was used to predict mutations that diminished or restored the extent of DNA curvature in the 59 regulatory region of ompS1. Using these predictions, curvature was diminished by sitedirected mutagenesis of only two residues, and curvature was restored by further mutagenesis of the same two residues. Lowering the extent of DNA curvature resulted in an increase in ompS1 expression and in the diminution of the affinity of the silencer proteins H-NS and StpA for the ompS1 59 regulatory region. These mutations were in a region shown not to contain the H-NS nucleation site, consistent with the notion that the effect on expression was due to changes in DNA structural topology. INTRODUCTIONSalmonella enterica serovar Typhi (S. Typhi) is the aetiological agent of typhoid fever in humans (Pang et al., 1998). In our laboratory we have identified the S. Typhi ompS1 gene that encodes the OmpS1 quiescent porin belonging to the OmpC/OmpF superfamily (Fernández-Mora et al., 1995). OmpS1 has been reported to have a role in swarming motility, biofilm formation and virulence in mice (Toguchi et al., 2000;Mireles et al., 2001;Rodríguez-Morales et al., 2006). Expression of ompS1 is dependent on two overlapping promoters, P1 and P2. The P1 promoter is dependent on the OmpR response regulator. The P2 promoter does not require OmpR for activation, being active only in the absence of OmpR (Oropeza et al., 1999; Flores-Valdez et al., 2003;De la Cruz et al., 2007). Another key element in the transcriptional regulation of ompS1 is the global regulatory protein H-NS, a nucleoid protein of 137 amino acids (15 kDa) that negatively regulates its expression (FloresValdez et al., 2003;De la Cruz et al., 2007). In Salmonella, H-NS has been proposed to selectively silence horizontally acquired genes by targeting sequences with a GC content lower than the resident genome, regulating around 12 % of its genes (Lucchini et al., 2006; Navarre et al., 2006). StpA, an H-NS paralogue, was found to repress ompS1 in an hns background; and LeuO, a LysR-type regulator, positively regulates ompS1 expression by antagonizing H-NS and StpA (De la Cruz et al., 2007). LeuO has been implicated in several functions, such as stress resistance, virulence and biofilm formation (VanBogelen et al., 1996;Fang et al., 2000;Majumder et al., 2001;Tenor et al., 2004; Lawley et al., 2006;Moorthy & Watnick, 2005;Rodríguez-Morales et al., 2006). Recently, our group has described several genes regulated by LeuO in S. Typhi (Hernández-Lucas et al., 2008).In bacterial genomes, the recognition of their binding targets by regulatory proteins is commonly considered to be sequence-dependent, although DNA curvature plays a well-characterized role in many transcriptional regulation mechanisms in pr...

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Association with pathogenic bacteria affects life‐history traits and population growth in Caenorhabditis elegans

Díaz

Mooring

Rens

et al. 2015

Ecology and Evolution

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Determining the relationship between individual life-history traits and population dynamics is an essential step to understand and predict natural selection. Model organisms that can be conveniently studied experimentally at both levels are invaluable to test the rich body of theoretical literature in this area. The nematode Caenorhabditis elegans, despite being a well-established workhorse in genetics, has only recently received attention from ecologists and evolutionary biologists, especially with respect to its association with pathogenic bacteria. In order to start filling the gap between the two areas, we conducted a series of experiments aiming at measuring life-history traits as well as population growth of C. elegans in response to three different bacterial strains: Escherichia coli OP50, Salmonella enterica Typhimurium, and Pseudomonas aeruginosa PAO1. Whereas previous studies had established that the latter two reduced the survival of nematodes feeding on them compared to E. coli OP50, we report for the first time an enhancement in reproductive success and population growth for worms feeding on S. enterica Typhimurium. Furthermore, we used an age-specific population dynamic model, parameterized using individual life-history assays, to successfully predict the growth of populations over three generations. This study paves the way for more detailed and quantitative experimental investigation of the ecology and evolution of C. elegans and the bacteria it interacts with, which could improve our understanding of the fate of opportunistic pathogens in the environment.

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Caenorhabditis elegans-Based Screen Identifies Salmonella Virulence Factors Required for Conserved Host-Pathogen Interactions

Cited by 133 publications

References 34 publications

Caenorhabditis elegans as a Model To Determine Fitness of Antibiotic-Resistant Salmonella enterica Serovar Typhimurium

Caenorhabditis elegans as a Model To Determine Fitness of Antibiotic-Resistant Salmonella enterica Serovar Typhimurium

The DNA static curvature has a role in the regulation of the ompS1 porin gene in Salmonella enterica serovar Typhi

Association with pathogenic bacteria affects life‐history traits and population growth in Caenorhabditis elegans

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