Iron ERRs with Salmonella

The hormone hepcidin promotes iron sequestration by macrophages. A recent study by Kim et al. (2014) implicates the orphan receptor ERRγ (estrogen-related receptor γ) in the regulation of hepcidin production and suggests that targeting the ERRγ-hepcidin axis may be beneficial during infection with the facultative intracellular pathogen Salmonella

Do individual and institutional predictors of misconduct vary by country? Results of a matched-control analysis of problematic image duplications

Pressures to publish, perverse incentives, financial interest and gender are amongst the most commonly discussed risk factors for scientific misconduct. However, evidence of their association with actual data fabrication and falsification is inconclusive. A recent case-controlled analysis of articles containing problematic image duplications suggested that country of affiliation of first and last authors is a significant predictor of scientific misconduct. The same analysis found null or negative associations with individual proxies of publication rate, impact and gender. The latter findings, in line with previous evidence, failed to support common hypotheses about the prevalence and causes of misconduct, but country-level effects may have confounded these results. Here we extend and complete previous results by comparing, via matched-controls analysis, articles from authors in the same country. We found that evidence for individual-level risk factors may be significant in some countries, and null or opposite in others. In particular, in countries where publications are rewarded with cash incentives, and especially China, the risk of problematic image duplication was higher for more productive, more frequently cited, earlier-career researchers working in lower-ranking institutions, in accordance with a "misaligned incentives"explanation for scientific misconduct. However, a null or opposite pattern was observed in all other countries, and especially the USA, UK and Canada, countries where concerns for misaligned incentives are commonly expressed. In line with previous results, we failed to observe a statistically significant association with industry funding and with gender. This is the first direct evidence of a link between publication performance and risk of misconduct and between university ranking and risk of misconduct. Commonly hypothesised individual risk factors for scientific misconduct, including career status and productivity, might be relevant in countries where cashreward policies generate perverse incentives. In most scientifically active countries, however, where other incentives systems are in place, these patterns are not observed, and other risk factors might be more relevant. Policies to prevent and correct scientific misconduct may need to be tailored to a countries' or institutions' specific context

Testing hypotheses on risk factors for scientific misconduct via matched-control analysis of papers containing problematic image duplications

It is commonly hypothesized that scientists are more likely to engage in data falsification and fabrication when they are subject to pressures to publish, when they are not restrained by forms of social control, when they work in countries lacking policies to tackle scientific misconduct, and when they are male. Evidence to test these hypotheses, however, is inconclusive due to the difficulties of obtaining unbiased data. Here we report a pre-registered test of these four hypotheses, conducted on papers that were identified in a previous study as containing problematic image duplications through a systematic screening of the journal PLoS ONE. Image duplications were classified into three categories based on their complexity, with category 1 being most likely to reflect unintentional error and category 3 being most likely to reflect intentional fabrication. We tested multiple parameters connected to the hypotheses above with a matched-control paradigm, by collecting two controls for each paper containing duplications. Category 1 duplications were mostly not associated with any of the parameters tested, as was predicted based on the assumption that these duplications were mostly not due to misconduct. Categories 2 and 3, however, exhibited numerous statistically significant associations. Results of univariable and multivariable analyses support the hypotheses that academic culture, peer control, cash-based publication incentives and national misconduct policies might affect scientific integrity. No clear support was found for the “pressures to publish” hypothesis. Female authors were found to be equally likely to publish duplicated images compared to males. Country-level parameters generally exhibited stronger effects than individual-level parameters, because developing countries were significantly more likely to produce problematic image duplications. This suggests that promoting good research practices in all countries should be a priority for the international research integrity agenda

Biology and Clinical Significance of Virulence Plasmids in Salmonella Serovars

Non-typhoid Salmonella strains containing virulence plasmids are highly associated with bacteremia and disseminated infection in humans. These plasmids are found in Salmonella serovars adapted to domestic animals, such as Salmonella dublin and Salmonella choleraesuis, as well as in the widely distributed pathogens Salmonella typhimurium and Salmonella enteritidis. Although virulence plasmids differ between serovars, all contain a highly conserved 8-kb region containing the spv locus that encodes the spvR regulatory gene and four structural spvABCD genes. Studies in mice suggest that the spv genes enhance the ability of Salmonella strains to grow within cells of the reticuloendothelial system. The spv genes are not expressed during exponential growth in vitro but are rapidly induced following entry of Salmonella strains into mammalian cells, including macrophages. Transcription of the spv genes is controlled by the stationary-phase (T factor RpoS, and mutations in RpoS abolish virulence. These studies suggest that the ability of Salmonella strains to respond to starvation stress in the host tissues is an essential component of virulenc

Antimicrobial Actions of the Nadph Phagocyte Oxidase and Inducible Nitric Oxide Synthase in Experimental Salmonellosis. II. Effects on Microbial Proliferation and Host Survival in Vivo

The roles of the NADPH phagocyte oxidase (phox) and inducible nitric oxide synthase (iNOS) in host resistance to virulent Salmonella typhimurium were investigated in gp91phox−/−, iNOS−/−, and congenic wild-type mice. Although both gp91phox−/− and iNOS−/− mice demonstrated increased susceptibility to infection with S. typhimurium compared with wild-type mice, the kinetics of bacterial replication were dramatically different in the gp91phox−/− and iNOS−/− mouse strains. Greater bacterial numbers were present in the spleens and livers of gp91phox−/− mice compared with C57BL/6 controls as early as day 1 of infection, and all of the gp91phox−/− mice succumbed to infection within 5 d. In contrast, an increased bacterial burden was detected within reticuloendothelial organs of iNOS−/− mice only beyond the first week of infection. Influx of inflammatory CD11b+ cells, granuloma formation, and serum interferon γ levels were unimpaired in iNOS−/− mice, but the iNOS-deficient granulomas were unable to limit bacterial replication. The NADPH phagocye oxidase and iNOS are both required for host resistance to wild-type Salmonella, but appear to operate principally at different stages of infection

Vaccination with attenuated Salmonella enterica Dublin expressing E coli O157:H7 outer membrane protein Intimin induces transient reduction of fecal shedding of E coli O157:H7 in cattle

<p>Abstract</p> <p>Background</p> <p><it>Escherichia coli </it>serogroup O157:H7 has emerged as an important zoonotic bacterial pathogen, causing a range of symptoms from self-limiting bloody diarrhea to severe hemorrhagic colitis and hemolytic-uremic syndrome in humans. Beef and dairy cattle are considered the most important animal reservoirs for this pathogen. One of the important virulence characteristics of <it>E. coli </it>O157:H7 is the <it>eaeA </it>gene encoding the 97 kDa surface protein intimin. Intimin is required for attachment and effacement during the interaction of enterohemorrhagic <it>E. coli </it>with human and bovine neonatal enterocytes. The present study was undertaken to test the hypothesis that an adaptive mucosal immune response directed against intimin will reduce or prevent enteric colonization and fecal shedding of <it>E. coli </it>O157:H7 in cattle.</p> <p>Results</p> <p>Cattle were orally inoculated with either milk (control), milk with live attenuated <it>Salmonella enterica </it>serovar Dublin (vector), or milk with live attenuated recombinant <it>S</it>. Dublin expressing intimin (vaccinated) on days 0, 14 and 28. On day 98, all calves were challenged orally with <it>E. coli </it>O157:H7 to evaluate whether vaccination with the recombinant <it>S</it>. Dublin expressing intimin would reduce the level of <it>E. coli </it>O157:H7 fecal shedding.</p> <p>During the first 28 days, vaccinated calves shed both the vector strain and the intimin-expressing <it>S</it>. Dublin strain at a similar level. The vector strain was shed for a significantly longer period as compared to the level of recombinant vaccine strain. Calves that received the intimin-expressed vaccine ceased shedding <it>S</it>. Dublin from day 28 to day 63. All calves were challenged with <it>E. coli </it>O157:H7 on day 98 to determine the effect on fecal shedding of <it>E. coli </it>O157:H7. The amount of <it>E. coli </it>O157:H7 in feces was measured for 30 days post-challenge. We observed a transient clearance of <it>E. coli </it>O157:H7 from the feces in the vaccinated calves. The magnitude of fecal <it>E. coli </it>O157:H7 shedding did not correlate with the presence of intimin-specific fecal IgA.</p> <p>Conclusion</p> <p>Oral vaccination with live attenuated recombinant <it>S</it>. Dublin expressing intimin reduced enteric colonization and fecal shedding of <it>E. coli </it>O157:H7. However, the transient clearance of <it>E. coli </it>O157:H7 was not associated with an enhanced IgA-mediated mucosal immune response.</p

Taming the Elephant: Salmonella Biology, Pathogenesis, and Prevention

Salmonella infections continue to cause substantial morbidity and mortality throughout the world. However, recent discoveries and new paradigms promise to lead to novel strategies to diagnose, treat, and prevent Salmonella infections. This review provides an update of the Salmonella field based on oral presentations given at the recent 3rd ASM Conference on Salmonella: Biology, Pathogenesis and Prevention

PoxA, YjeK and Elongation Factor P Coordinately Modulate Virulence and Drug Resistance in \u3cem\u3eSalmonella enterica\u3c/em\u3e

We report an interaction between poxA, encoding a paralog of lysyl tRNA-synthetase, and the closely linked yjeK gene, encoding a putative 2,3-β-lysine aminomutase, that is critical for virulence and stress resistance in Salmonella enterica. Salmonella poxA and yjeK mutants share extensive phenotypic pleiotropy, including attenuated virulence in mice, an increased ability to respire under nutrient-limiting conditions, hypersusceptibility to a variety of diverse growth inhibitors, and altered expression of multiple proteins, including several encoded on the SPI-1 pathogenicity island. PoxA mediates posttranslational modification of bacterial elongation factor P (EF-P), analogous to the modification of the eukaryotic EF-P homolog, eIF5A, with hypusine. The modification of EF-P is a mechanism of regulation whereby PoxA acts as an aminoacyl-tRNA synthetase that attaches an amino acid to a protein resembling tRNA rather than to a tRNA

Multicopy Single-Stranded DNA Directs Intestinal Colonization of Enteric Pathogens

Multicopy single-stranded DNAs (msDNAs) are hybrid RNA-DNA molecules encoded on retroelements called retrons and produced by the action of retron reverse transcriptases. Retrons are widespread in bacteria but the natural function of msDNA has remained elusive despite 30 years of study. The major roadblock to elucidation of the function of these unique molecules has been the lack of any identifiable phenotypes for mutants unable to make msDNA. We report that msDNA of the zoonotic pathogen Salmonella Typhimurium is necessary for colonization of the intestine. Similarly, we observed a defect in intestinal persistence in an enteropathogenic E. coli mutant lacking its retron reverse transcriptase. Under anaerobic conditions in the absence of msDNA, proteins of central anaerobic metabolism needed for Salmonella colonization of the intestine are dysregulated. We show that the msDNA-deficient mutant can utilize nitrate, but not other alternate electron acceptors in anaerobic conditions. Consistent with the availability of nitrate in the inflamed gut, a neutrophilic inflammatory response partially rescued the ability of a mutant lacking msDNA to colonize the intestine. These findings together indicate that the mechanistic basis of msDNA function during Salmonella colonization of the intestine is proper production of proteins needed for anaerobic metabolism. We further conclude that a natural function of msDNA is to regulate protein abundance, the first attributable function for any msDNA. Our data provide novel insight into the function of this mysterious molecule that likely represents a new class of regulatory molecules