48 results on '"Sebbane, Florent"'
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2. What do we know about osmoadaptation of Yersinia pestis?
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Bontemps-Gallo, Sébastien, Lacroix, Jean-Marie, and Sebbane, Florent
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- 2022
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3. Characterization of the protective immune response to Yersinia pseudotuberculosis infection in mice vaccinated with an LcrV-secreting strain of Lactococcus lactis
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Daniel, Catherine, Titecat, Marie, Poiret, Sabine, Cayet, Delphine, Boutillier, Denise, Simonet, Michel, Sirard, Jean-Claude, Lemaître, Nadine, and Sebbane, Florent
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- 2016
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4. Transcriptomic studies and assessment of Yersinia pestis reference genes in various conditions
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Koch, Lionel, Poyot, Thomas, Schnetterle, Marine, Guillier, Sophie, Soulé, Estelle, Nolent, Flora, Gorgé, Olivier, Neulat-Ripoll, Fabienne, Valade, Eric, Sebbane, Florent, and Biot, Fabrice
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- 2019
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5. Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens.
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Zhao, Jinshi, Cochrane, C. Skyler, Najeeb, Javaria, Gooden, David, Sciandra, Carly, Fan, Ping, Lemaitre, Nadine, Newns, Kate, Nicholas, Robert A., Guan, Ziqiang, Thaden, Joshua T., Fowler Jr., Vance G., Spasojevic, Ivan, Sebbane, Florent, Toone, Eric J., Duncan, Clayton, Gammans, Richard, and Zhou, Pei
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GRAM-negative bacteria ,CARDIOTOXICITY ,URINARY tract infections ,LIPID synthesis ,ANTIBIOTICS assay ,BIOSYNTHESIS - Abstract
The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non–hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications. Editor's summary: Lipid A biosynthesis is essential to the formation of the outer membrane of most Gram-negative bacteria and has been considered a potential target for antibiotic therapy. Zhao et al. have now characterized an inhibitor (LPC-233) of the UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC, which can specifically inhibit lipid A synthesis. Previous attempts to make LpxC-targeting antibiotics were limited by unfavorable cardiovascular toxicity. In contrast, preclinical evaluation of LPC-233 revealed promising in vitro and in vivo safety profiles, tight binding to LpxC with picomolar affinity, oral bioavailability, and bactericidal activity against a broad range of Gram-negative pathogens. These results support the further development of LpxC-targeting antibiotic therapies. —Christiana Fogg [ABSTRACT FROM AUTHOR]
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- 2023
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6. Yersinia pestis Requires the 2-Component Regulatory System OmpR-EnvZ to Resist Innate Immunity During the Early and Late Stages of Plague
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Reboul, Angéline, Lemaître, Nadine, Titecat, Marie, Merchez, Maud, Deloison, Gaspard, Ricard, Isabelle, Pradel, Elizabeth, Marceau, Michaël, and Sebbane, Florent
- Published
- 2014
7. Inheritance of the Lysozyme Inhibitor Ivy Was an Important Evolutionary Step by Yersinia pestis to Avoid the Host Innate Immune Response
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Derbise, Anne, Pierre, François, Merchez, Maud, Pradel, Elizabeth, Laouami, Sabrina, Ricard, Isabelle, Sirard, Jean-Claude, Fritz, Jill, Lemaître, Nadine, Akinbi, Henry, Boneca, Ivo G., and Sebbane, Florent
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- 2013
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8. Adaptive Response of Yersinia pestis to Extracellular Effectors of Innate Immunity during Bubonic Plague
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Sebbane, Florent, Lemaître, Nadine, Sturdevant, Daniel E., Rebeil, Roberto, Virtaneva, Kimmo, Porcella, Stephen F., and Hinnebusch, B. Joseph
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- 2006
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9. Role of the Yersinia pestis Plasminogen Activator in the Incidence of Distinct Septicemic and Bubonic Forms of Flea-Borne Plague
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Sebbane, Florent, Jarrett, Clayton O., Gardner, Donald, Long, Daniel, and Hinnebusch, B. Joseph
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- 2006
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10. Poor Vector Competence of Fleas and the Evolution of Hypervirulence in Yersinia pestis
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Lorange, Ellen A., Race, Brent L., Sebbane, Florent, and Hinnebusch, B. Joseph
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- 2005
11. Yersinia pestis and Plague: Some Knowns and Unknowns.
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Yang, Ruifu, Atkinson, Steve, Chen, Ziqi, Cui, Yujun, Du, Zongmin, Han, Yanping, Sebbane, Florent, Slavin, Philip, Song, Yajun, Yan, Yanfeng, Wu, Yarong, Xu, Lei, Zhang, Chutian, Zhang, Yun, Hinnebusch, B. Joseph, Stenseth, Nils Chr., and Motin, Vladimir L.
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YERSINIA pestis ,BIOTERRORISM ,GENETIC regulation ,PATHOGENIC microorganisms - Abstract
Since its first identification in 1894 during the third pandemic in Hong Kong, there has been significant progress in understanding the lifestyle of Yersinia pestis, the pathogen that is responsible for plague. Although we now have some understanding of the pathogen's physiology, genetics, genomics, evolution, gene regulation, pathogenesis and immunity, there are many unknown aspects of the pathogen and its disease development. Here, we focus on some of the knowns and unknowns related to Y. pestis and plague. We notably focus on some key Y. pestis physiologic and virulence traits that are important for its mammal-flea-mammal life cycle, but also its emergence from the enteropathogen, Yersinia pseudotuberculosis. Some aspects of the genetic diversity of Y. pestis, the distribution and ecology of plague, as well as the medical countermeasures to protect our population are also provided. Lastly, we present some biosafety and biosecurity information related to Y. pestis and plague. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Genes encoding specific nickel transfort systems flank the chromosomal urease locus of pathogenic yersiniae
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Sebbane, Florent, Mandrand-Berthelot, Marie-Andree, and Simonet, Michel
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Microbial enzymes -- Genetic aspects ,Nickel -- Physiological aspects ,Metalloenzymes ,Bacteria, Pathogenic -- Physiological aspects ,Bacteria, Pathogenic -- Genetic aspects ,Enzymes ,Biological sciences - Abstract
Research reveals that Yersinia pseudotuberculosis produces two types of nickel-specific transporters, whose loci are located on each side of the urease gene cluster flanking 5'and 3' ends. The transport systems are a multicomponent ABC nickel transporter encoded by the yntABCDE locus and a single-component transporter encoded by the ureH gene.
- Published
- 2002
13. The superantigen gene ypm is located in an unstable chromosomal locus of Yersinia pseudotuberculosis
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Carnoy, Christophe, Floquet, Stephanie, Marceau, Michael, Sebbane, Florent, Haentjens-Herwegh, Stephanie, Devalckenaere, Annie, and Simonet, Michael
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Bacterial genetics -- Research ,Mitogens -- Genetic aspects ,Genetic regulation -- Analysis ,Chromosome deletion -- Physiological aspects ,Biological sciences - Abstract
Research shows that the superantigen gene ypm, encoding Yersinia pseudotuberculosis-derived mitogen, is not associated with mobile genetic elements and inserts into the bacterial genome in an unstable locus on the chromosome. Data indicate that DNA deletion in this locus occurs with high frequency.
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- 2002
14. The Yersinia pseudotuberculosis Yut protein, a new type of urea transporter homologous to eukaryotic channels and functionally interchangeable in vitro with the Helicobacter pylori UreI protein
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Sebbane, Florent, Bury-Moné, Stéphanie, Cailliau, Katia, Browaeys-Poly, Edith, De Reuse, Hilde, and Simonet, Michel
- Published
- 2002
15. Emergence and spread of ancestral Yersinia pestis in Late-Neolithic and Bronze-Age Eurasia, ca. 5,000 to 2,500 y B.P.
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Slavin, Philip and Sebbane, Florent
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YERSINIA pestis , *YERSINIA pseudotuberculosis , *FOOD contamination , *NOMADS , *ANCESTORS - Published
- 2022
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16. A refined model of how Yersinia pestis produces a transmissible infection in its flea vector.
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Dewitte, Amélie, Bouvenot, Typhanie, Pierre, François, Ricard, Isabelle, Pradel, Elizabeth, Barois, Nicolas, Hujeux, Anaïs, Bontemps-Gallo, Sébastien, and Sebbane, Florent
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YERSINIA pestis ,FLEAS ,ECTOPARASITES ,GENETIC techniques ,INFECTION ,MASS production - Abstract
In flea-borne plague, blockage of the flea's foregut by Yersinia pestis hastens transmission to the mammalian host. Based on microscopy observations, we first suggest that flea blockage results from primary infection of the foregut and not from midgut colonization. In this model, flea infection is characterized by the recurrent production of a mass that fills the lumen of the proventriculus and encompasses a large number of Y. pestis. This recurrence phase ends when the proventricular cast is hard enough to block blood ingestion. We further showed that ymt (known to be essential for flea infection) is crucial for cast production, whereas the hmsHFRS operon (known to be essential for the formation of the biofilm that blocks the gut) is needed for cast consolidation. By screening a library of mutants (each lacking a locus previously known to be upregulated in the flea gut) for biofilm formation, we found that rpiA is important for flea blockage but not for colonization of the midgut. This locus may initially be required to resist toxic compounds within the proventricular cast. However, once the bacterium has adapted to the flea, rpiA helps to form the biofilm that consolidates the proventricular cast. Lastly, we used genetic techniques to demonstrate that ribose-5-phosphate isomerase activity (due to the recent gain of a second copy of rpiA (y2892)) accentuated blockage but not midgut colonization. It is noteworthy that rpiA is an ancestral gene, hmsHFRS and rpiA2 were acquired by the recent ancestor of Y. pestis, and ymt was acquired by Y. pestis itself. Our present results (i) highlight the physiopathological and molecular mechanisms leading to flea blockage, (ii) show that the role of a gene like rpiA changes in space and in time during an infection, and (iii) emphasize that evolution is a gradual process punctuated by sudden jumps. Author summary: Plague is a deadly flea-borne disease caused by the bacillus Yersinia pestis. This bacterium blocks the flea's foregut (proventriculus) to increase its likelihood of being regurgitated by fleas trying to take a blood meal. Understanding the mechanisms leading to flea blockage may help to find ways of controlling plague. Here, we propose a model in which blockage results from primary infection of the foregut and not from midgut colonization. In the proventriculus, Y. pestis induces, resists and then consolidates the formation of a bactericidal matrix that can be recurrently dislodged by a blood meal before it becomes firmly anchored to the proventriculus and thus definitively obstructs it. Induction, resistance, and then consolidation of the mass in the proventriculus were made possible by the sequential acquisition of genetic material by the ancestors of Y. pestis and by Y. pestis itself–emphasizing that evolution is a gradual process punctuated by sudden jumps. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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17. Nutrient depletion may trigger the Yersinia pestis OmpR‐EnvZ regulatory system to promote flea‐borne plague transmission.
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Bontemps‐Gallo, Sébastien, Fernandez, Marion, Dewitte, Amélie, Raphaël, Etienne, Gherardini, Frank C., Elizabeth, Pradel, Koch, Lionel, Biot, Fabrice, Reboul, Angéline, and Sebbane, Florent
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YERSINIA pestis ,PLAGUE ,HARMONIC oscillators ,ECTOPARASITES ,PATTERN matching ,FLEAS ,DISEASE vectors - Abstract
Summary: The flea's lumen gut is a poorly documented environment where the agent of flea‐borne plague, Yersinia pestis, must replicate to produce a transmissible infection. Here, we report that both the acidic pH and osmolarity of the lumen's contents display simple harmonic oscillations with different periods. Since an acidic pH and osmolarity are two of three known stimuli of the OmpR‐EnvZ two‐component system in bacteria, we investigated the role and function of this Y. pestis system in fleas. By monitoring the in vivo expression pattern of three OmpR‐EnvZ‐regulated genes, we concluded that the flea gut environment triggers OmpR‐EnvZ. This activation was not, however, correlated with changes in pH and osmolarity but matched the pattern of nutrient depletion (the third known stimulus for OmpR‐EnvZ). Lastly, we found that the OmpR‐EnvZ and the OmpF porin are needed to produce the biofilm that ultimately obstructs the flea's gut and thus hastens the flea‐borne transmission of plague. Taken as a whole, our data suggest that the flea gut is a complex, fluctuating environment in which Y. pestis senses nutrient depletion via OmpR‐EnvZ. Once activated, the latter triggers a molecular program (including at least OmpF) that produces the biofilm required for efficient plague transmission. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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18. Reply to Alfani: Reconstructing past plague ecology to understand human history.
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Stenseth, Nils Chr., Bramanti, Barbara, Büntgen, Ulf, Fell, Henry G., Cohn, Samuel, Sebbane, Florent, Slavin, Philip, Chutian Zhang, Ruifu Yang, and Lei Xu
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HUMAN ecology ,EARTH system science - Published
- 2023
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19. Polymorphism in the Yersinia LcrV Antigen Enables Immune Escape From the Protection Conferred by an LcrV-Secreting Lactococcus Lactis in a Pseudotuberculosis Mouse Model.
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Daniel, Catherine, Dewitte, Amélie, Poiret, Sabine, Marceau, Michaël, Simonet, Michel, Marceau, Laure, Descombes, Guillaume, Boutillier, Denise, Bennaceur, Nadia, Bontemps-Gallo, Sébastien, Lemaître, Nadine, and Sebbane, Florent
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LACTOCOCCUS lactis ,YERSINIA ,YERSINIA pestis ,YERSINIA enterocolitica ,YERSINIA pseudotuberculosis ,ANTIGENS - Abstract
Yersinioses caused by Yersinia pestis, Yersinia pseudotuberculosis , and Yersinia enterocolitica are significant concerns in human and veterinary health. The link between virulence and the potent LcrV antigen has prompted the latter's selection as a major component of anti- Yersinia vaccines. Here, we report that (i) the group of Yersinia species encompassing Y. pestis and Y. pseudotuberculosis produces at least five different clades of LcrV and (ii) vaccination of mice with an LcrV-secreting Lactococcus lactis only protected against Yersinia strains producing the same LcrV clade as that of used for vaccination. By vaccinating with engineered LcrVs and challenging mice with strains producing either type of LcrV or a LcrV mutated for regions of interest, we highlight key polymorphic residues responsible for the absence of cross-protection. Our results show that an anti-LcrV-based vaccine should contain multiple LcrV clades if protection against the widest possible array of Yersinia strains is sought. [ABSTRACT FROM AUTHOR]
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- 2019
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20. To block or not to block: The adaptive manipulation of plague transmission.
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Gandon, Sylvain, Heitzmann, Louise, and Sebbane, Florent
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PLAGUE ,INFECTIOUS disease transmission ,BIOFILMS - Abstract
The ability of the agent of plague, Yersinia pestis, to form a biofilm blocking the gut of the flea has been considered to be a key evolutionary step in maintaining flea‐borne transmission. However, blockage decreases dramatically the life expectancy of fleas, challenging the adaptive nature of blockage. Here, we develop an epidemiological model of plague that accounts for its different transmission routes, as well as the within‐host competition taking place between bacteria within the flea vector. We use this theoretical framework to identify the environmental conditions promoting the evolution of blockage. We also show that blockage is favored at the onset of an epidemic, and that the frequencies of bacterial strains exhibiting different strategies of blockage can fluctuate in seasonal environments. This analysis quantifies the contribution of different transmission routes in plague and makes testable predictions on the adaptive nature of blockage. [ABSTRACT FROM AUTHOR]
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- 2019
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21. Protection against Yersinia pseudotuberculosis infection conferred by a Lactococcus lactis mucosal delivery vector secreting LcrV
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Daniel, Catherine, Sebbane, Florent, Poiret, Sabine, Goudercourt, Denise, Dewulf, Joelle, Mullet, Chantal, Simonet, Michel, and Pot, Bruno
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- 2009
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22. High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors.
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Titecat, Marie, Xiaofei Liang, Chul-Jin Lee, Charlet, Audrey, Hocquet, Didier, Lambert, Thierry, Pagès, Jean-Marie, Courcol, René, Sebbane, Florent, Toone, Eric J., Pei Zhou, Lemaitre, Nadine, Liang, Xiaofei, Lee, Chul-Jin, and Zhou, Pei
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GRAM-negative bacteria ,PATHOGENIC microorganisms ,ANAPHYLAXIS ,BIPHENYL compounds ,DIFLUOROMETHYL compounds ,AMIDASES ,ANTIBIOTICS ,BACTERIAL proteins ,DRUG resistance in microorganisms ,ENTEROBACTERIACEAE ,ENZYME inhibitors ,ESCHERICHIA coli ,HYDROLASES ,KLEBSIELLA ,MICROBIAL sensitivity tests ,PSEUDOMONAS ,RESEARCH funding ,HYDROXY acids ,ENTEROBACTERIACEAE diseases ,THREONINE ,GRAM-negative aerobic bacteria ,IN vitro studies ,CHEMICAL inhibitors ,PHARMACODYNAMICS - Abstract
Objectives: Inhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC, which catalyses the first, irreversible step in lipid A biosynthesis) are a promising new class of antibiotics against Gram-negative bacteria. The objectives of the present study were to: (i) compare the antibiotic activities of three LpxC inhibitors (LPC-058, LPC-011 and LPC-087) and the reference inhibitor CHIR-090 against Gram-negative bacilli (including MDR and XDR isolates); and (ii) investigate the effect of combining these inhibitors with conventional antibiotics.Methods: MICs were determined for 369 clinical isolates (234 Enterobacteriaceae and 135 non-fermentative Gram-negative bacilli). Time-kill assays with LPC-058 were performed on four MDR/XDR strains, including Escherichia coli producing CTX-M-15 ESBL and Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii producing KPC-2, VIM-1 and OXA-23 carbapenemases, respectively.Results: LPC-058 was the most potent antibiotic and displayed the broadest spectrum of antimicrobial activity, with MIC90 values for Enterobacteriaceae, P. aeruginosa, Burkholderia cepacia and A. baumannii of 0.12, 0.5, 1 and 1 mg/L, respectively. LPC-058 was bactericidal at 1× or 2× MIC against CTX-M-15, KPC-2 and VIM-1 carbapenemase-producing strains and bacteriostatic at ≤4× MIC against OXA-23 carbapenemase-producing A. baumannii. Combinations of LPC-058 with β-lactams, amikacin and ciprofloxacin were synergistic against these strains, albeit in a species-dependent manner. LPC-058's high efficacy was attributed to the presence of the difluoromethyl-allo-threonyl head group and a linear biphenyl-diacetylene tail group.Conclusions: These in vitro data highlight the therapeutic potential of the new LpxC inhibitor LPC-058 against MDR/XDR strains and set the stage for subsequent in vivo studies. [ABSTRACT FROM AUTHOR]- Published
- 2016
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23. New Insights into How Yersinia pestis Adapts to Its Mammalian Host during Bubonic Plague.
- Author
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Pradel, Elizabeth, Lemaître, Nadine, Merchez, Maud, Ricard, Isabelle, Reboul, Angéline, Dewitte, Amélie, and Sebbane, Florent
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YERSINIA pestis genetics ,PLAGUE ,MICROBIAL virulence ,GENETIC transformation ,PUBLIC health - Abstract
Bubonic plague (a fatal, flea-transmitted disease) remains an international public health concern. Although our understanding of the pathogenesis of bubonic plague has improved significantly over the last few decades, researchers have still not been able to define the complete set of Y. pestis genes needed for disease or to characterize the mechanisms that enable infection. Here, we generated a library of Y. pestis mutants, each lacking one or more of the genes previously identified as being up-regulated in vivo. We then screened the library for attenuated virulence in rodent models of bubonic plague. Importantly, we tested mutants both individually and using a novel, “per-pool” screening method that we have developed. Our data showed that in addition to genes involved in physiological adaption and resistance to the stress generated by the host, several previously uncharacterized genes are required for virulence. One of these genes (ympt1.66c, which encodes a putative helicase) has been acquired by horizontal gene transfer. Deletion of ympt1.66c reduced Y. pestis' ability to spread to the lymph nodes draining the dermal inoculation site – probably because loss of this gene decreased the bacteria's ability to survive inside macrophages. Our results suggest that (i) intracellular survival during the early stage of infection is important for plague and (ii) horizontal gene transfer was crucial in the acquisition of this ability. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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24. Efficacy of Ciprofloxacin-Gentamicin Combination Therapy in Murine Bubonic Plague.
- Author
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Lemaître, Nadine, Ricard, Isabelle, Pradel, Elizabeth, Foligné, Benoît, Courcol, René, Simonet, Michel, and Sebbane, Florent
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ANTIBIOTICS ,PLAGUE ,CIPROFLOXACIN ,GENTAMICIN ,YERSINIA pestis ,LYMPH nodes - Abstract
Potential benefits of combination antibiotic therapy for the treatment of plague have never been evaluated. We compared the efficacy of a ciprofloxacin (CIN) and gentamicin (GEN) combination therapy with that of each antibiotic administered alone (i) against Yersinia pestis in vitro and (ii) in a mouse model of bubonic plague in which animals were intravenously injected with antibiotics for five days, starting at two different times after infection (44 h and 56 h). In vitro, the CIN+GEN combination was synergistic at 0.5x the individual drugs' MICs and indifferent at 1x- or 2x MIC. In vivo, the survival rate for mice treated with CIN+GEN was similar to that observed with CIN alone and slightly higher than that observed for GEN alone 100, 100 and 85%, respectively when treatment was started 44 h post challenge. 100% of survivors were recorded in the CIN+GEN group vs 86 and 83% in the CIN and GEN groups, respectively when treatment was delayed to 56 h postchallenge. However, these differences were not statistically significant. Five days after the end of treatment, Y. pestis were observed in lymph nodes draining the inoculation site (but not in the spleen) in surviving mice in each of the three groups. The median lymph node log
10 CFU recovered from persistently infected lymph nodes was significantly higher with GEN than with CIN (5.8 vs. 3.2, p=0.04) or CIN+GEN (5.8 vs. 2.8, p=0.01). Taken as the whole, our data show that CIN+GEN combination is as effective as CIN alone but, regimens containing CIN are more effective to eradicate Y. pestis from the draining lymph node than the recommended GEN monotherapy. Moreover, draining lymph nodes may serve as a reservoir for the continued release of Y. pestis into the blood - even after five days of intravenous antibiotic treatment. [ABSTRACT FROM AUTHOR]- Published
- 2012
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25. Role of the Yersinia pestis Yersiniabactin Iron Acquisition System in the Incidence of Flea-Borne Plague.
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Sebbane, Florent, Jarrett, Clayton, Gardner, Donald, Long, Daniel, and Hinnebusch, B. Joseph
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PLAGUE , *YERSINIA pestis , *BACTERIOLOGY , *HISTOLOGY , *YERSINIA diseases , *COMMUNICABLE diseases , *EPIDEMICS , *YERSINIA , *MICROBIOLOGY , *ANATOMY - Abstract
Plague is a flea-borne zoonosis caused by the bacterium Yersinia pestis. Y. pestis mutants lacking the yersiniabactin (Ybt) siderophore-based iron transport system are avirulent when inoculated intradermally but fully virulent when inoculated intravenously in mice. Presumably, Ybt is required to provide sufficient iron at the peripheral injection site, suggesting that Ybt would be an essential virulence factor for flea-borne plague. Here, using a flea-to-mouse transmission model, we show that a Y. pestis strain lacking the Ybt system causes fatal plague at low incidence when transmitted by fleas. Bacteriology and histology analyses revealed that a Ybt-negative strain caused only primary septicemic plague and atypical bubonic plague instead of the typical bubonic form of disease. The results provide new evidence that primary septicemic plague is a distinct clinical entity and suggest that unusual forms of plague may be caused by atypical Y. pestis strains. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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26. Autophagosomes can support Yersinia pseudotuberculosis replication in macrophages.
- Author
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Moreau, Kevin, Lacas-Gervais, Sandra, Fujita, Naonobu, Sebbane, Florent, Yoshimori, Tamotsu, Simonet, Michel, and Lafont, Frank
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PHAGOSOMES ,YERSINIA pseudotuberculosis ,MACROPHAGES ,CELL proliferation ,PATHOGENIC microorganisms - Abstract
Yersinia pseudotuberculosis is able to replicate inside macrophages. However, the intracellular trafficking of the pathogen after its entry into the macrophage remains poorly understood. Using in vitro infected bone marrow-derived macrophages, we show that Y. pseudotuberculosis activates the autophagy pathway. Host cell autophagosomes subverted by bacteria do not become acidified and sustain bacteria replication. Moreover, we report that autophagy inhibition correlated with bacterial trafficking inside an acidic compartment. This study indicates that Y. pseudotuberculosis hijacks the autophagy pathway for its replication and also opens up new opportunities for deciphering the molecular basis of the host cell signalling response to intracellular Yersinia infection. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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27. Transit through the Flea Vector Induces a Pretransmission Innate Immunity Resistance Phenotype in Yersinia pestis.
- Author
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Vadyvaloo, Viveka, Jarrett, Clayton, Sturdevant, Daniel E., Sebbane, Florent, and Hinnebusch, B. Joseph
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MAMMAL anatomy ,IMMUNOREGULATION ,NATURAL immunity ,PHENOTYPES ,YERSINIA pestis - Abstract
Yersinia pestis, the agent of plague, is transmitted to mammals by infected fleas. Y. pestis exhibits a distinct life stage in the flea, where it grows in the form of a cohesive biofilm that promotes transmission. After transmission, the temperature shift to 37°C induces many known virulence factors of Y. pestis that confer resistance to innate immunity. These factors are not produced in the low-temperature environment of the flea, however, suggesting that Y. pestis is vulnerable to the initial encounter with innate immune cells at the flea bite site. In this study, we used whole-genome microarrays to compare the Y. pestis in vivo transcriptome in infective fleas to in vitro transcriptomes in temperature-matched biofilm and planktonic cultures, and to the previously characterized in vivo gene expression profile in the rat bubo. In addition to genes involved in metabolic adaptation to the flea gut and biofilm formation, several genes with known or predicted roles in resistance to innate immunity and pathogenicity in the mammal were upregulated in the flea. Y. pestis from infected fleas were more resistant to phagocytosis by macrophages than in vitro-grown bacteria, in part attributable to a cluster of insecticidal-like toxin genes that were highly expressed only in the flea. Our results suggest that transit through the flea vector induces a phenotype that enhances survival and dissemination of Y. pestis after transmission to the mammalian host. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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28. Antibiotic Therapy of Plague: A Review.
- Author
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Sebbane, Florent, Lemaître, Nadine, and Anisimov, Andrey P.
- Subjects
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ANTIBIOTICS , *LACTAMS , *BETA lactam antibiotics , *RIFAMYCINS , *YERSINIA pestis , *PUBLIC health , *CHLORAMPHENICOL - Abstract
Plague—a deadly disease caused by the bacterium Yersinia pestis—is still an international public health concern. There are three main clinical forms: bubonic plague, septicemic plague, and pulmonary plague. In all three forms, the symptoms appear suddenly and progress very rapidly. Early antibiotic therapy is essential for countering the disease. Several classes of antibiotics (e.g., tetracyclines, fluoroquinolones, aminoglycosides, sulfonamides, chloramphenicol, rifamycin, and β-lactams) are active in vitro against the majority of Y. pestis strains and have demonstrated efficacy in various animal models. However, some discrepancies have been reported. Hence, health authorities have approved and recommended several drugs for prophylactic or curative use. Only monotherapy is currently recommended; combination therapy has not shown any benefits in preclinical studies or case reports. Concerns about the emergence of multidrug-resistant strains of Y. pestis have led to the development of new classes of antibiotics and other therapeutics (e.g., LpxC inhibitors, cationic peptides, antivirulence drugs, predatory bacteria, phages, immunotherapy, host-directed therapy, and nutritional immunity). It is difficult to know which of the currently available treatments or therapeutics in development will be most effective for a given form of plague. This is due to the lack of standardization in preclinical studies, conflicting data from case reports, and the small number of clinical trials performed to date. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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29. Yersinia pestis Plasminogen Activator.
- Author
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Sebbane, Florent, Uversky, Vladimir N., and Anisimov, Andrey P.
- Subjects
- *
PLASMINOGEN activators , *YERSINIA pestis , *GRAM-negative bacteria , *PLASMINOGEN , *NATURAL immunity , *PLAGUE - Abstract
The Gram-negative bacterium Yersinia pestis causes plague, a fatal flea-borne anthropozoonosis, which can progress to aerosol-transmitted pneumonia. Y. pestis overcomes the innate immunity of its host thanks to many pathogenicity factors, including plasminogen activator, Pla. This factor is a broad-spectrum outer membrane protease also acting as adhesin and invasin. Y. pestis uses Pla adhesion and proteolytic capacity to manipulate the fibrinolytic cascade and immune system to produce bacteremia necessary for pathogen transmission via fleabite or aerosols. Because of microevolution, Y. pestis invasiveness has increased significantly after a single amino-acid substitution (I259T) in Pla of one of the oldest Y. pestis phylogenetic groups. This mutation caused a better ability to activate plasminogen. In paradox with its fibrinolytic activity, Pla cleaves and inactivates the tissue factor pathway inhibitor (TFPI), a key inhibitor of the coagulation cascade. This function in the plague remains enigmatic. Pla (or pla) had been used as a specific marker of Y. pestis, but its solitary detection is no longer valid as this gene is present in other species of Enterobacteriaceae. Though recovering hosts generate anti-Pla antibodies, Pla is not a good subunit vaccine. However, its deletion increases the safety of attenuated Y. pestis strains, providing a means to generate a safe live plague vaccine. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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30. Body Lice, Yersinia pestis Orientalis, and Black Death.
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Ayyadurai, Saravanan, Sebbane, Florent, Raoult, Didier, and Drancourt, Michel
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- *
LETTERS to the editor , *YERSINIA pestis , *BLACK Death pandemic, 1348-1351 - Abstract
A letter to the editor is presented about body lice, Yersinia pestis Orientalis, and the occurrence of Black Death resulting from the plague outbreak.
- Published
- 2010
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31. Drug design from the cryptic inhibitor envelope.
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Lee, Chul-Jin, Liang, Xiaofei, Wu, Qinglin, Najeeb, Javaria, Zhao, Jinshi, Gopalaswamy, Ramesh, Titecat, Marie, Sebbane, Florent, Lemaitre, Nadine, Toone, Eric J., and Zhou, Pei
- Published
- 2016
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32. AWidefield Light Microscopy-Based Approach Provides Further Insights into the Colonization of the Flea Proventriculus by Yersinia pestis.
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Dewitte, Amélie, Werkmeister, Elisabeth, Pierre, François, Sebbane, Florent, and Bontemps-Gallo, Sébastien
- Subjects
- *
YERSINIA pestis , *FLEAS , *RODENT populations , *IMAGE analysis , *FOREGUT - Abstract
Yersinia pestis (the agent of flea-borne plague) must obstruct the flea's proventriculus to maintain transmission to a mammalian host. To this end, Y. pestis must consolidate a mass that entrapped Y. pestis within the proventriculus very early after its ingestion. We developed a semiautomated fluorescent image analysis method and used it to monitor and compare colonization of the flea proventriculus by a fully competent flea-blocking Y. pestis strain, a partially competent strain, and a noncompetent strain. Our data suggested that flea blockage results primarily from the replication of Y. pestis trapped in the anterior half of the proventriculus. However, consolidation of the bacteriaentrapping mass and colonization of the entire proventricular lumen increased the likelihood of flea blockage. The data also showed that consolidation of the bacterial mass is not a prerequisite for colonization of the proventriculus but allowed Y. pestis to maintain itself in a large flea population for an extended period of time. Taken as the whole, the data suggest that a strategy targeting bacterial mass consolidation could significantly reduce the likelihood of Y. pestis being transmitted by fleas (due to gut blockage), but also the possibility of using fleas as a long-term reservoir. IMPORTANCE: Yersinia pestis (the causative agent of plague) is one of the deadliest bacterial pathogens. It circulates primarily among rodent populations and their fleas. Better knowledge of the mechanisms leading to the flea-borne transmission of Y. pestis is likely to generate strategies for controlling or even eradicating this bacillus. It is known that Y. pestis obstructs the flea's foregut so that the insect starves, frantically bites its mammalian host, and regurgitates Y. pestis at the bite site. Here, we developed a semiautomated fluorescent image analysis method and used it to document and compare foregut colonization and disease progression in fleas infected with a fully competent fleablocking Y. pestis strain, a partially competent strain, and a noncompetent strain. Overall, our data provided new insights into Y. pestis' obstruction of the proventriculus for transmission but also the ecology of plague. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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33. Functional and Structural Analysis of HicA3-HicB3, a Novel Toxin-Antitoxin System of Yersinia pestis.
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Bibi-Triki, Sabrina, de la Sierra-Gallay, Inès Li, Lazar, Noureddine, Leroy, Arnaud, Van Tilbeurgh, Herman, Sebbane, Florent, and Pradel, Elizabeth
- Subjects
- *
YERSINIA pestis , *ANTITOXINS , *MUTAGENESIS , *RIBONUCLEASES , *GENETIC transcription in bacteria , *CRYSTAL structure research - Abstract
The mechanisms involved in the virulence of Yersinia pestis, the plague pathogen, are not fully understood. In previous research, we found that a Y. pestis mutant lacking the HicB3 (YPO3369) putative orphan antitoxin was attenuated for virulence in a murine model of bubonic plague. Toxin-antitoxin systems (TASs) are widespread in prokaryotes. Most bacterial species possess many TASs of several types. In type II TASs, the toxin protein is bound and neutralized by its cognate antitoxin protein in the cytoplasm. Here we identify the hicA3 gene encoding the toxin neutralized by HicB3 and show that HicA3-HicB3 constitutes a new functional type II TAS in Y. pestis. Using biochemical and mutagenesis-based approaches, we demonstrate that the HicA3 toxin is an RNase with a catalytic histidine residue. HicB3 has two functions: it sequesters and neutralizes HicA3 by blocking its active site, and it represses transcription of the hicA3B3 operon. Gel shift assays and reporter fusion experiments indicate that the HicB3 antitoxin binds to two operators in the hicA3B3 promoter region. We solved the X-ray structures of HicB3 and the HicA3-HicB3 complex; thus, we present the first crystal structure of a TA complex from the HicAB family. HicB3 forms a tetramer that can bind two HicA3 toxin molecules. HicA3 is monomeric and folds as a double-stranded-RNA-binding domain. The HicB3 N-terminal domain occludes the HicA3 active site, whereas its C-terminal domain folds as a ribbon-helix-helix DNA-binding motif. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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34. The CpxAR signaling system confers a fitness advantage for flea gut colonization by the plague bacillus.
- Author
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Robin B, Dewitte A, Alaimo V, Lecoeur C, Pierre F, Billon G, Sebbane F, and Bontemps-Gallo S
- Subjects
- Animals, Plague microbiology, Copper metabolism, Copper pharmacology, Oxidative Stress, Hydrogen Peroxide metabolism, Hydrogen Peroxide pharmacology, Insect Vectors microbiology, Protein Kinases, Yersinia pestis genetics, Yersinia pestis metabolism, Bacterial Proteins genetics, Bacterial Proteins metabolism, Signal Transduction, Siphonaptera microbiology, Gene Expression Regulation, Bacterial, Gastrointestinal Tract microbiology
- Abstract
The adaptation of Yersinia pestis , the flea-borne plague agent, to fluctuating environmental conditions is essential for the successful colonization of the flea vector. A previous comparative transcriptomic analysis showed that the Cpx pathway of Y. pestis is up-regulated in infected fleas. The CpxAR two-component system is a component of the envelope stress response and is critical for maintaining the integrity of the cell. Here, a phenotypic screening revealed a survival defect of the cpxAR mutant to oxidative stress and copper. The measured copper concentration in the digestive tract contents of fed fleas increased fourfold during the digestive process. By direct analysis of phosphorylation of CpxR by a Phos-Tag gel approach, we demonstrated that biologically relevant concentrations of copper triggered the system. Then, a competitive challenge highlighted the role of the CpxAR system in bacterial fitness during flea infection. Lastly, an in vitro sequential exposure to copper and then H
2 O2 to mimic the flea suggests a model in which, within the insect digestive tract, the CpxAR system would be triggered by copper, establishing an oxidative stress response., Importance: The bacterium Yersinia pestis is the agent of flea-borne plague. Our knowledge of the mechanisms used by the plague bacillus to infect the flea vector is limited. The up-regulation of the envelope stress response under the control of the Cpx signaling pathway was previously shown in a transcriptomic study. Here, our in vivo and in vitro approaches suggest a model in which Y. pestis uses the CpxAR phosphorelay system to sense and respond to the copper present in the flea gut, thereby optimizing the flea gut colonization. In other words, the system is essential for bacterial fitness in the flea., Competing Interests: The authors declare no conflict of interest.- Published
- 2024
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35. No evidence for persistent natural plague reservoirs in historical and modern Europe.
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Stenseth NC, Tao Y, Zhang C, Bramanti B, Büntgen U, Cong X, Cui Y, Zhou H, Dawson LA, Mooney SJ, Li D, Fell HG, Cohn S, Sebbane F, Slavin P, Liang W, Tong H, Yang R, and Xu L
- Subjects
- Humans, Europe, Pandemics history, Climate, Soil, Disease Reservoirs, Plague epidemiology, Plague history, Yersinia pestis
- Abstract
Caused by Yersinia pestis , plague ravaged the world through three known pandemics: the First or the Justinianic (6th-8th century); the Second (beginning with the Black Death during c.1338-1353 and lasting until the 19th century); and the Third (which became global in 1894). It is debatable whether Y. pestis persisted in European wildlife reservoirs or was repeatedly introduced from outside Europe (as covered by European Union and the British Isles). Here, we analyze environmental data (soil characteristics and climate) from active Chinese plague reservoirs to assess whether such environmental conditions in Europe had ever supported "natural plague reservoirs". We have used new statistical methods which are validated through predicting the presence of modern plague reservoirs in the western United States. We find no support for persistent natural plague reservoirs in either historical or modern Europe. Two factors make Europe unfavorable for long-term plague reservoirs: 1) Soil texture and biochemistry and 2) low rodent diversity. By comparing rodent communities in Europe with those in China and the United States, we conclude that a lack of suitable host species might be the main reason for the absence of plague reservoirs in Europe today. These findings support the hypothesis that long-term plague reservoirs did not exist in Europe and therefore question the importance of wildlife rodent species as the primary plague hosts in Europe.
- Published
- 2022
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36. What do we know about osmoadaptation of Yersinia pestis?
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Bontemps-Gallo S, Lacroix JM, and Sebbane F
- Subjects
- Adaptation, Physiological, Animals, Insect Vectors, Plague, Siphonaptera, Yersinia pestis genetics
- Abstract
The plague agent Yersinia pestis mainly spreads among mammalian hosts and their associated fleas. Production of a successful mammal-flea-mammal life cycle implies that Y. pestis senses and responds to distinct cues in both host and vector. Among these cues, osmolarity is a fundamental parameter. The plague bacillus lives in a tightly regulated environment in the mammalian host, while osmolarity fluctuates in the flea gut (300-550 mOsM). Here, we review the mechanisms that enable Y. pestis to perceive fluctuations in osmolarity, as well as genomic plasticity and physiological adaptation of the bacterium to this stress., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2021
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37. Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC.
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Lemaître N, Liang X, Najeeb J, Lee CJ, Titecat M, Leteurtre E, Simonet M, Toone EJ, Zhou P, and Sebbane F
- Subjects
- Animals, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Bacterial Proteins genetics, Benzamides chemistry, Benzamides pharmacology, Disease Models, Animal, Drug Resistance, Multiple, Bacterial, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Female, Gram-Negative Bacteria enzymology, Gram-Negative Bacterial Infections drug therapy, Gram-Negative Bacterial Infections microbiology, Lipid A biosynthesis, Mice, Morpholines chemistry, Morpholines pharmacology, Plague microbiology, Yersinia pestis enzymology, Anti-Bacterial Agents therapeutic use, Bacterial Proteins antagonists & inhibitors, Benzamides therapeutic use, Enzyme Inhibitors therapeutic use, Gram-Negative Bacteria drug effects, Morpholines therapeutic use, Plague drug therapy, Yersinia pestis drug effects
- Abstract
The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains., (Copyright © 2017 Lemaître et al.)
- Published
- 2017
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38. Evaluation of the Role of the opgGH Operon in Yersinia pseudotuberculosis and Its Deletion during the Emergence of Yersinia pestis.
- Author
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Quintard K, Dewitte A, Reboul A, Madec E, Bontemps-Gallo S, Dondeyne J, Marceau M, Simonet M, Lacroix JM, and Sebbane F
- Subjects
- Animals, Blotting, Western, Disease Models, Animal, Gene Deletion, Glucans biosynthesis, Glucans genetics, Mice, Operon genetics, Periplasmic Proteins biosynthesis, Periplasmic Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Bacterial Proteins genetics, Evolution, Molecular, Yersinia pestis pathogenicity, Yersinia pseudotuberculosis genetics, Yersinia pseudotuberculosis pathogenicity
- Abstract
The opgGH operon encodes glucosyltransferases that synthesize osmoregulated periplasmic glucans (OPGs) from UDP-glucose, using acyl carrier protein (ACP) as a cofactor. OPGs are required for motility, biofilm formation, and virulence in various bacteria. OpgH also sequesters FtsZ in order to regulate cell size according to nutrient availability. Yersinia pestis (the agent of flea-borne plague) lost the opgGH operon during its emergence from the enteropathogen Yersinia pseudotuberculosis. When expressed in OPG-negative strains of Escherichia coli and Dickeya dadantii, opgGH from Y. pseudotuberculosis restored OPGs synthesis, motility, and virulence. However, Y. pseudotuberculosis did not produce OPGs (i) under various growth conditions or (ii) when overexpressing its opgGH operon, its galUF operon (governing UDP-glucose), or the opgGH operon or Acp from E. coli. A ΔopgGH Y. pseudotuberculosis strain showed normal motility, biofilm formation, resistance to polymyxin and macrophages, and virulence but was smaller. Consistently, Y. pestis was smaller than Y. pseudotuberculosis when cultured at ≥ 37°C, except when the plague bacillus expressed opgGH. Y. pestis expressing opgGH grew normally in serum and within macrophages and was fully virulent in mice, suggesting that small cell size was not advantageous in the mammalian host. Lastly, Y. pestis expressing opgGH was able to infect Xenopsylla cheopis fleas normally. Our results suggest an evolutionary scenario whereby an ancestral Yersinia strain lost a factor required for OPG biosynthesis but kept opgGH (to regulate cell size). The opgGH operon was presumably then lost because OpgH-dependent cell size control became unnecessary., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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39. Superantigenic Yersinia pseudotuberculosis induces the expression of granzymes and perforin by CD4+ T cells.
- Author
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Goubard A, Loïez C, Abe J, Fichel C, Herwegh S, Faveeuw C, Porte R, Cayet D, Sebbane F, Penet S, Foligné B, Desreumaux P, Saito H, Sirard JC, Simonet M, and Carnoy C
- Subjects
- Animals, Gene Expression Profiling, Liver immunology, Liver pathology, Mice, Inbred BALB C, Spleen immunology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets microbiology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes microbiology, Granzymes metabolism, Pore Forming Cytotoxic Proteins metabolism, Superantigens immunology, Yersinia pseudotuberculosis immunology
- Abstract
Bacterial superantigens (SAgs) are immunostimulatory toxins that induce acute diseases mainly through the massive release of inflammatory cytokines. Yersinia pseudotuberculosis is the only Gram-negative bacterium known to produce a SAg (Y. pseudotuberculosis-derived mitogen [YPM]). This SAg binds major histocompatibility complex class II molecules on antigen-presenting cells and T cell receptors (TcR) bearing the variable region Vβ3, Vβ9, Vβ13.1, or Vβ13.2 (in humans) and Vβ7 or Vβ8 (in mice). We have previously shown that YPM exacerbates the virulence of Y. pseudotuberculosis in mice. With a view to understanding the mechanism of YPM's toxicity, we compared the immune response in BALB/c mice infected with a YPM-producing Y. pseudotuberculosis or the corresponding isogenic, SAg-deficient mutant. Five days after infection, we observed strong CD4(+) Vβ7(+) T cell expansion and marked interleukin-4 (IL-4) production in mice inoculated with SAg-producing Y. pseudotuberculosis. These phenomena were correlated with the activation of ypm gene transcription in liver and spleen. A transcriptomic analysis revealed that the presence of YPM also increased expression of granzyme and perforin genes in the host's liver and spleen. This expression was attributed to a CD4(+) T cell subset, rather than to natural killer T (NKT) cells that display a TcR with a Vβ region that is potentially recognized by YPM. Increased production of cytotoxic molecules was correlated with hepatotoxicity, as demonstrated by an increase in plasma alanine aminotransferase activity. Our results demonstrate that YPM activates a potentially hepatotoxic CD4(+) T cell population., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Published
- 2015
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40. New insights into how Yersinia pestis adapts to its mammalian host during bubonic plague.
- Author
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Pradel E, Lemaître N, Merchez M, Ricard I, Reboul A, Dewitte A, and Sebbane F
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Macrophages microbiology, Rats, Virulence, Host-Parasite Interactions genetics, Plague genetics, Yersinia pestis genetics, Yersinia pestis pathogenicity
- Abstract
Bubonic plague (a fatal, flea-transmitted disease) remains an international public health concern. Although our understanding of the pathogenesis of bubonic plague has improved significantly over the last few decades, researchers have still not been able to define the complete set of Y. pestis genes needed for disease or to characterize the mechanisms that enable infection. Here, we generated a library of Y. pestis mutants, each lacking one or more of the genes previously identified as being up-regulated in vivo. We then screened the library for attenuated virulence in rodent models of bubonic plague. Importantly, we tested mutants both individually and using a novel, "per-pool" screening method that we have developed. Our data showed that in addition to genes involved in physiological adaptation and resistance to the stress generated by the host, several previously uncharacterized genes are required for virulence. One of these genes (ympt1.66c, which encodes a putative helicase) has been acquired by horizontal gene transfer. Deletion of ympt1.66c reduced Y. pestis' ability to spread to the lymph nodes draining the dermal inoculation site--probably because loss of this gene decreased the bacteria's ability to survive inside macrophages. Our results suggest that (i) intracellular survival during the early stage of infection is important for plague and (ii) horizontal gene transfer was crucial in the acquisition of this ability.
- Published
- 2014
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41. TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3(neg)CD127+ immune cells in spleen and mucosa.
- Author
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Van Maele L, Carnoy C, Cayet D, Songhet P, Dumoutier L, Ferrero I, Janot L, Erard F, Bertout J, Leger H, Sebbane F, Benecke A, Renauld JC, Hardt WD, Ryffel B, and Sirard JC
- Subjects
- Animals, CD3 Complex genetics, CD3 Complex immunology, CD3 Complex metabolism, Cells, Cultured, Dendritic Cells drug effects, Dendritic Cells immunology, Dendritic Cells metabolism, Female, Flagellin pharmacology, Flow Cytometry, Gene Expression drug effects, Gene Expression immunology, Ileum drug effects, Ileum immunology, Ileum metabolism, Interleukin-17 genetics, Interleukin-17 metabolism, Interleukin-7 Receptor alpha Subunit genetics, Interleukin-7 Receptor alpha Subunit immunology, Interleukin-7 Receptor alpha Subunit metabolism, Interleukins genetics, Interleukins metabolism, Lymphoid Tissue cytology, Lymphoid Tissue immunology, Lymphoid Tissue metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Mice, Transgenic, Mucous Membrane cytology, Mucous Membrane metabolism, Oligonucleotide Array Sequence Analysis, Spleen cytology, Spleen metabolism, Toll-Like Receptor 5 genetics, Toll-Like Receptor 5 metabolism, Interleukin-22, Interleukin-17 immunology, Interleukins immunology, Mucous Membrane immunology, Signal Transduction immunology, Spleen immunology, Toll-Like Receptor 5 immunology
- Abstract
In adaptive immunity, Th17 lymphocytes produce the IL-17 and IL-22 cytokines that stimulate mucosal antimicrobial defenses and tissue repair. In this study, we observed that the TLR5 agonist flagellin induced swift and transient transcription of genes encoding IL-17 and IL-22 in lymphoid, gut, and lung tissues. This innate response also temporarily enhanced the expression of genes associated with the antimicrobial Th17 signature. The source of the Th17-related cytokines was identified as novel populations of CD3(neg)CD127(+) immune cells among which CD4-expressing cells resembling lymphoid tissue inducer cells. We also demonstrated that dendritic cells are essential for expression of Th17-related cytokines and so for stimulation of innate cells. These data define that TLR-induced activation of CD3(neg)CD127(+) cells and production of Th17-related cytokines may be crucial for the early defenses against pathogen invasion of host tissues.
- Published
- 2010
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42. The Yersinia pestis caf1M1A1 fimbrial capsule operon promotes transmission by flea bite in a mouse model of bubonic plague.
- Author
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Sebbane F, Jarrett C, Gardner D, Long D, and Hinnebusch BJ
- Subjects
- Animals, Disease Models, Animal, Fimbriae Proteins genetics, Mice, Mutation, Operon genetics, Virulence, Yersinia pestis pathogenicity, Bacterial Proteins genetics, Insect Bites and Stings microbiology, Plague genetics, Plague transmission, Siphonaptera microbiology, Yersinia pestis genetics
- Abstract
Plague is a zoonosis transmitted by fleas and caused by the gram-negative bacterium Yersinia pestis. During infection, the plasmidic caf1M1A1 operon that encodes the Y. pestis F1 protein capsule is highly expressed, and anti-F1 antibodies are protective. Surprisingly, the capsule is not required for virulence after injection of cultured bacteria, even though it is an antiphagocytic factor and capsule-deficient Y. pestis strains are rarely isolated. We found that a caf-negative Y. pestis mutant was not impaired in either flea colonization or virulence in mice after intradermal inoculation of cultured bacteria. In contrast, absence of the caf operon decreased bubonic plague incidence after a flea bite. Successful development of plague in mice infected by flea bite with the caf-negative mutant required a higher number of infective bites per challenge. In addition, the mutant displayed a highly autoaggregative phenotype in infected liver and spleen. The results suggest that acquisition of the caf locus via horizontal transfer by an ancestral Y. pestis strain increased transmissibility and the potential for epidemic spread. In addition, our data support a model in which atypical caf-negative strains could emerge during climatic conditions that favor a high flea burden. Human infection with such strains would not be diagnosed by the standard clinical tests that detect F1 antibody or antigen, suggesting that more comprehensive surveillance for atypical Y. pestis strains in plague foci may be necessary. The results also highlight the importance of studying Y. pestis pathogenesis in the natural context of arthropod-borne transmission.
- Published
- 2009
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43. Analysis of Yersinia pestis gene expression in the flea vector.
- Author
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Vadyvaloo V, Jarrett C, Sturdevant D, Sebbane F, and Hinnebusch BJ
- Subjects
- Animals, Biofilms growth & development, Biogenic Polyamines metabolism, Biological Transport, Active genetics, Gene Expression, Genes, Bacterial, Humans, Mutation, Plague microbiology, Plague transmission, RNA, Bacterial genetics, RNA, Bacterial isolation & purification, Virulence genetics, Virulence physiology, Yersinia pestis physiology, Insect Vectors microbiology, Siphonaptera microbiology, Yersinia pestis genetics, Yersinia pestis pathogenicity
- Abstract
Yersinia pestis is the causative agent of plague. Unlike the other pathogenic Yersinia species, Y. pestis has evolved an arthropod-borne route of transmission, alternately infecting flea and mammalian hosts. Distinct subsets of genes are hypothesized to be differentially expressed during infection of the arthropod vector and mammalian host. Genes crucial for mammalian infection are referred to as virulence factors whilst genes playing a role in the flea vector are termed transmission factors. This article serves as a review of known factors involved in flea-borne transmission and introduces an 'in vivo' microarray approach to elucidating the genetic basis of Y. pestis infection of- and transmission by the flea.
- Published
- 2007
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44. Yersinia pestis YopJ suppresses tumor necrosis factor alpha induction and contributes to apoptosis of immune cells in the lymph node but is not required for virulence in a rat model of bubonic plague.
- Author
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Lemaître N, Sebbane F, Long D, and Hinnebusch BJ
- Subjects
- Animals, Apoptosis, Bacterial Proteins genetics, Blood immunology, Blood microbiology, Disease Models, Animal, Female, Immunity, Innate, Lymph Nodes microbiology, Lymph Nodes pathology, Mutation, Plague pathology, Rats, Rats, Inbred Strains, Sequence Deletion, Spleen microbiology, Spleen pathology, Tumor Necrosis Factor-alpha analysis, Virulence genetics, Virulence Factors metabolism, Yersinia pestis genetics, Bacterial Proteins physiology, Plague immunology, Plague microbiology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Yersinia pestis pathogenicity
- Abstract
The virulence of the pathogenic Yersinia species depends on a plasmid-encoded type III secretion system that transfers six Yop effector proteins into host cells. One of these proteins, YopJ, has been shown to disrupt host cell signaling pathways involved in proinflammatory cytokine production and to induce macrophage apoptosis in vitro. YopJ-dependent apoptosis in mesenteric lymph nodes has also been demonstrated in a mouse model of Yersinia pseudotuberculosis infection. These results suggest that YopJ attenuates the host innate and adaptive immune response during infection, but the role of YopJ during bubonic plague has not been completely established. We evaluated the role of Yersinia pestis YopJ in a rat model of bubonic plague following intradermal infection with a fully virulent Y. pestis strain and an isogenic yopJ mutant. Deletion of yopJ resulted in a twofold decrease in the number of apoptotic immune cells in the bubo and a threefold increase in serum tumor necrosis factor alpha levels but did not result in decreased virulence, systemic spread, or colonization levels in the spleen and blood. Our results indicate that YopJ is not essential for bubonic plague pathogenesis, even after peripheral inoculation of low doses of Y. pestis. Instead, the effects of YopJ appear to overlap and augment the immunomodulatory effects of other Y. pestis virulence factors.
- Published
- 2006
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45. Kinetics of disease progression and host response in a rat model of bubonic plague.
- Author
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Sebbane F, Gardner D, Long D, Gowen BB, and Hinnebusch BJ
- Subjects
- Animals, Blood microbiology, Colony Count, Microbial, Disease Progression, Disease Susceptibility, Female, Kinetics, Lymph Nodes microbiology, Lymph Nodes pathology, Lymphatic Diseases microbiology, Lymphatic Diseases pathology, Lymphatic Diseases physiopathology, Plague immunology, Plague microbiology, Plague pathology, Rats, Rats, Inbred Strains, Species Specificity, Spleen microbiology, Spleen pathology, Yersinia pestis isolation & purification, Antibodies, Bacterial biosynthesis, Plague physiopathology
- Abstract
Plague, caused by the gram-negative bacterium Yersinia pestis, primarily affects rodents but is also an important zoonotic disease of humans. Bubonic plague in humans follows transmission by infected fleas and is characterized by an acute, necrotizing lymphadenitis in the regional lymph nodes that drain the intradermal flea bite site. Septicemia rapidly follows with spread to spleen, liver, and other organs. We developed a model of bubonic plague using the inbred Brown Norway strain of Rattus norvegicus to characterize the progression and kinetics of infection and the host immune response after intradermal inoculation of Y. pestis. The clinical signs and pathology in the rat closely resembled descriptions of human bubonic plague. The bacteriology; histopathology; host cellular response in infected lymph nodes, blood, and spleen; and serum cytokine levels were analyzed at various times after infection to determine the kinetics and route of disease progression and to evaluate hypothesized Y. pestis pathogenic mechanisms. Understanding disease progression in this rat infection model should facilitate further investigations into the molecular pathogenesis of bubonic plague and the immune response to Y. pestis at different stages of the disease.
- Published
- 2005
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46. Evaluation of the role of constitutive isocitrate lyase activity in Yersinia pestis infection of the flea vector and mammalian host.
- Author
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Sebbane F, Jarrett CO, Linkenhoker JR, and Hinnebusch BJ
- Subjects
- Animals, Mice, Virulence, Yersinia pseudotuberculosis pathogenicity, Insect Vectors microbiology, Isocitrate Lyase physiology, Siphonaptera microbiology, Yersinia pestis enzymology, Yersinia pestis pathogenicity
- Abstract
Yersinia pestis, unlike the closely related Yersinia pseudotuberculosis, constitutively produces isocitrate lyase (ICL). Here we show that the Y. pestis aceA homologue encodes ICL and is required for growth on acetate but not for flea infection or virulence in mice. Thus, deregulation of the glyoxylate pathway does not underlie the recent adaptation of Y. pestis to arthropod-borne transmission.
- Published
- 2004
- Full Text
- View/download PDF
47. Flea-borne transmission model to evaluate vaccine efficacy against naturally acquired bubonic plague.
- Author
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Jarrett CO, Sebbane F, Adamovicz JJ, Andrews GP, and Hinnebusch BJ
- Subjects
- Animals, Antibodies, Bacterial blood, Antigens, Bacterial immunology, Bacterial Proteins immunology, Disease Models, Animal, Humans, Mice, Mice, Hairless, Plague microbiology, Plague Vaccine immunology, Pore Forming Cytotoxic Proteins, Insect Vectors microbiology, Plague prevention & control, Plague transmission, Plague Vaccine administration & dosage, Siphonaptera microbiology, Yersinia pestis immunology
- Abstract
A flea-to-mouse transmission model was developed for use in testing new candidate vaccines for the ability to protect against flea-borne plague. The model was used to evaluate a recombinant fusion protein vaccine consisting of the Yersinia pestis F1 and V antigens. After one to three challenges with Y. pestis-infected fleas, 14 of 15 unvaccinated control mice developed plague, with an average septicemia level of 9.2 x 10(8) Y. pestis CFU/ml. None of 15 vaccinated mice developed the disease after similar challenges, and serological testing indicated that transmitted bacteria were eliminated by the immune system before extensive replication and systemic infection could occur. The transmission and development of disease in control mice correlated with the number of bites by blocked fleas but not with the total number of fleabites. The model provides a means to directly assess the efficacy of new vaccines to prevent naturally acquired bubonic plague and to study events at the vector-host interface that lead to dissemination and disease.
- Published
- 2004
- Full Text
- View/download PDF
48. Function and regulation of the Salmonella-like pmrF antimicrobial peptide resistance operon in Yersinia pseudotuberculosis.
- Author
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Marceau M, Sebbane F, Collyn F, and Simonet M
- Subjects
- Animals, Disease Models, Animal, Mice, Salmonella typhimurium drug effects, Salmonella typhimurium genetics, Species Specificity, Transcription, Genetic, Virulence, Yersinia pseudotuberculosis drug effects, Yersinia pseudotuberculosis Infections physiopathology, Anti-Bacterial Agents pharmacology, Drug Resistance, Bacterial genetics, Operon genetics, Peptides, Yersinia pseudotuberculosis genetics
- Published
- 2003
- Full Text
- View/download PDF
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