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Integral and peripheral association of proteins and protein complexes with Yersinia pestis inner and outer membranes
Rembert Pieper, Shih-Ting Huang, David J Clark, Jeffrey M Robinson, Hamid Alami, Prashanth P Parmar, Moo-Jin Suh, Srilatha Kuntumalla, Christine L Bunai, Robert D Perry, Robert D Fleischmann, Scott N Peterson
Proteome Science , 2009, DOI: 10.1186/1477-5956-7-5
Abstract: Yersinia pestis, a Gram-negative bacterium, is the causative agent of the bubonic and pneumonic plague. The pathogenic lifestyle of this microbe involves two distinct life stages, one in the flea vector, the other in mammalian hosts, primarily rodents [1]. Humans are a dead-end host and not part of the flea-mammal cycle. Y. pestis strains associated with high virulence have been divided into three classical biovars (antiqua, mediaevalis and orientalis) based on differences in their abilities to ferment glycerol and reduce nitrate. A fourth biovar (microtus) has been proposed on the basis of low virulence and reduced transmission [2-4]. Complete DNA sequence data exist for the genomes of each of these four biovars [5-8]. The gene organization and complete DNA sequences of three Y. pestis virulence-associated plasmids were also determined [9,10]. The pCD1 plasmid, shared with other human pathogenic Yersinia species, encodes a suite of proteins required for a functional type III secretion system (T3SS) and host infection. A temperature increase from 26–30 to 37°C and host cell contact or a low Ca2+ concentration induce expression of these proteins [11]. Most Y. pestis strains harbor two unique plasmids, pPCP1 and pMT1, not present in Y. pseudotuberculosis. These plasmids encode factors such as the plasminogen activator protease (Pla), required for mammalian pathogenesis [12], the Yersinia murine toxin (Ymt), required for colonization of the mid-gut of fleas [13,14], and the F1 capsular antigen (Caf1) [15]. The F1 antigen causes in vitro resistance to phagocytosis, but its role in mammalian virulence is unclear [16]. In addition, the genetically unstable chromosomal 102-kb pgm locus is important for full virulence of the bubonic plague in mammals and for transmission via blocked fleas [17,18]. It encodes the yersiniabactin siderophore-dependent iron transport (Ybt) system [19,20] and the Hms-dependent biofilm system. Biofilm formation allows colonization of the flea pro
Fibrinolytic and coagulative activities of Yersinia pestis  [PDF]
Timo K. Korhonen
Frontiers in Cellular and Infection Microbiology , 2013, DOI: 10.3389/fcimb.2013.00035
Abstract: The outer membrane protease Pla belongs to the omptin protease family spread by horizontal gene transfer into Gram-negative bacteria that infect animals or plants. Pla has adapted to support the life style of the plague bacterium Yersinia pestis. Pla has a β-barrel fold with 10 membrane-spanning β strands and five surface loops, and the barrel surface contains bound lipopolysaccharide (LPS) that is critical for the conformation and the activity of Pla. The biological activity of Pla is influenced by the structure of the surface loops around the active site groove and by temperature-induced LPS modifications. Several of the putative virulence-related functions documented for Pla in vitro address control of the human hemostatic system, i.e., coagulation and fibrinolysis. Pla activates human plasminogen to the serine protease plasmin and activates the physiological plasminogen activator urokinase. Pla also inactivates the protease inhibitors alpha-2-antiplasmin and plasminogen activator inhibitor 1 (PAI-1) and prevents the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). These functions enhance uncontrolled fibrinolysis which is thought to improve Y. pestis dissemination and survival in the mammalian host, and lowered fibrin(ogen) deposition has indeed been observed in mice infected with Pla-positive Y. pestis. However, Pla also inactivates an anticoagulant, the tissue factor (TF) pathway inhibitor, which should increase fibrin formation and clotting. Thus, Pla and Y. pestis have complex interactions with the hemostatic system. Y. pestis modifies its LPS upon transfer to the mammalian host and we hypothesize that the contrasting biological activities of Pla in coagulation and fibrinolysis are influenced by LPS changes during infection.
A review of plague persistence with special emphasis on fleas  [PDF]
Jeffrey Wimsatt,Dean E. Biggins
Journal of Vector Borne Diseases , 2009,
Abstract: Sylvatic plague is highly prevalent during infrequent epizootics that ravage the landscape of western North America. During these periods, plague dissemination is very efficient. Epizootics end when rodent and flea populations are decimated and vectored transmission declines. A second phase (enzootic plague) ensues when plague is difficult to detect from fleas, hosts or the environment, and presents less of a threat to public health. Recently, researchers have hypothesized that the bacterium (Yersinia pestis) responsible for plague maintains a continuous state of high virulence and thus only changes in transmission efficiency explain the shift between alternating enzootic and epizootic phases. However, if virulent transmission becomes too inefficient, strong selection might favor an alternate survival strategy. Another plausible non-exclusive hypothesis, best supported from Asian field studies, is that Y. pestis persists (locally) at foci by maintaining a more benign relationship within adapted rodents during the long expanses of time between outbreaks. From this vantage, it can revert to the epizootic (transmission efficient) form. Similarly, in the United States (US), enzootic plague persistence has been proposed to develop sequestered within New World rodent carriers. However, the absence of clear support for rodent carriers in North America has encouraged a broader search for alternative explanations. A telluric plague existence has been proposed. However, the availability of flea life stages and their hosts could critically supplement environmental plague sources, or fleas might directly represent a lowlevel plague reservoir. Here, we note a potentially pivotal role for fleas. These epizootic plague vectors should be closely studied with newer more exacting methods to determine their potential to serve as participants in or accomplices to a plague persistence reservoir.
Diagnosis of plague and identification of virulence markers in Yersinia pestis by multiplex-PCR
LEAL, Nilma C.;ALMEIDA, Alzira M. P. de;
Revista do Instituto de Medicina Tropical de S?o Paulo , 1999, DOI: 10.1590/S0036-46651999000600002
Abstract: we have developed a procedure for the rapid diagnosis of plague that also allows the identification of prominent virulence markers of y. pestis strains. this procedure is based upon the use of a single polymerase chain reaction with multiple pairs of primers directed at genes present in the three virulence plasmids as well as in the chromosomal pathogenicity island of the bacterium. the technique allowed the discrimination of strains which lacked one or more of the known pathogenic loci, using as template total dna obtained from bacterial cultures and from simulated blood cultures containing diluted concentration of bacteria. it also proved effective in confirming the disease in a blood culture from a plague suspected patient. as the results are obtained in a few hours this technique will be useful in the methodology of the plague control program.
Diagnosis of plague and identification of virulence markers in Yersinia pestis by multiplex-PCR  [cached]
LEAL Nilma C.,ALMEIDA Alzira M. P. de
Revista do Instituto de Medicina Tropical de S?o Paulo , 1999,
Abstract: We have developed a procedure for the rapid diagnosis of plague that also allows the identification of prominent virulence markers of Y. pestis strains. This procedure is based upon the use of a single polymerase chain reaction with multiple pairs of primers directed at genes present in the three virulence plasmids as well as in the chromosomal pathogenicity island of the bacterium. The technique allowed the discrimination of strains which lacked one or more of the known pathogenic loci, using as template total DNA obtained from bacterial cultures and from simulated blood cultures containing diluted concentration of bacteria. It also proved effective in confirming the disease in a blood culture from a plague suspected patient. As the results are obtained in a few hours this technique will be useful in the methodology of the Plague Control Program.
Fast and Simple Detection of Yersinia pestis Applicable to Field Investigation of Plague Foci  [PDF]
Stéphanie Simon, Christian Demeure, Patricia Lamourette, Sofia Filali, Marc Plaisance, Christophe Créminon, Hervé Volland, Elisabeth Carniel
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054947
Abstract: Yersinia pestis, the plague bacillus, has a rodent-flea-rodent life cycle but can also persist in the environment for various periods of time. There is now a convenient and effective test (F1-dipstick) for the rapid identification of Y. pestis from human patient or rodent samples, but this test cannot be applied to environmental or flea materials because the F1 capsule is mostly produced at 37°C. The plasminogen activator (PLA), a key virulence factor encoded by a Y. pestis-specific plasmid, is synthesized both at 20°C and 37°C, making it a good candidate antigen for environmental detection of Y. pestis by immunological methods. A recombinant PLA protein from Y. pestis synthesized by an Escherichia coli strain was used to produce monoclonal antibodies (mAbs). PLA-specific mAbs devoid of cross-reactions with other homologous proteins were further cloned. A pair of mAbs was selected based on its specificity, sensitivity, comprehensiveness, and ability to react with Y. pestis strains grown at different temperatures. These antibodies were used to develop a highly sensitive one-step PLA-enzyme immunoassay (PLA-EIA) and an immunostrip (PLA-dipstick), usable as a rapid test under field conditions. These two PLA-immunometric tests could be valuable, in addition to the F1-disptick, to confirm human plague diagnosis in non-endemic areas (WHO standard case definition). They have the supplementary advantage of allowing a rapid and easy detection of Y. pestis in environmental and flea samples, and would therefore be of great value for surveillance and epidemiological investigations of plague foci. Finally, they will be able to detect natural or genetically engineered F1-negative Y. pestis strains in human patients and environmental samples.
Role of the Yersinia pestis Yersiniabactin Iron Acquisition System in the Incidence of Flea-Borne Plague  [PDF]
Florent Sebbane,Clayton Jarrett,Donald Gardner,Daniel Long,B. Joseph Hinnebusch
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014379
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.
Dissociation of Tissue Destruction and Bacterial Expansion during Bubonic Plague  [PDF]
Fran?oise Guinet?,Patrick Avé?,Sofia Filali?,Christèle Huon?,Cyril Savin?,Michel Huerre?,Laurence Fiette?,Elisabeth Carniel
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1005222
Abstract: Activation and/or recruitment of the host plasmin, a fibrinolytic enzyme also active on extracellular matrix components, is a common invasive strategy of bacterial pathogens. Yersinia pestis, the bubonic plague agent, expresses the multifunctional surface protease Pla, which activates plasmin and inactivates fibrinolysis inhibitors. Pla is encoded by the pPla plasmid. Following intradermal inoculation, Y. pestis has the capacity to multiply in and cause destruction of the lymph node (LN) draining the entry site. The closely related, pPla-negative, Y. pseudotuberculosis species lacks this capacity. We hypothesized that tissue damage and bacterial multiplication occurring in the LN during bubonic plague were linked and both driven by pPla. Using a set of pPla-positive and pPla-negative Y. pestis and Y. pseudotuberculosis strains in a mouse model of intradermal injection, we found that pPla is not required for bacterial translocation to the LN. We also observed that a pPla-cured Y. pestis caused the same extensive histological lesions as the wild type strain. Furthermore, the Y. pseudotuberculosis histological pattern, characterized by infectious foci limited by inflammatory cell infiltrates with normal tissue density and follicular organization, was unchanged after introduction of pPla. However, the presence of pPla enabled Y. pseudotuberculosis to increase its bacterial load up to that of Y. pestis. Similarly, lack of pPla strongly reduced Y. pestis titers in LNs of infected mice. This pPla-mediated enhancing effect on bacterial load was directly dependent on the proteolytic activity of Pla. Immunohistochemistry of Pla-negative Y. pestis-infected LNs revealed extensive bacterial lysis, unlike the numerous, apparently intact, microorganisms seen in wild type Y. pestis-infected preparations. Therefore, our study demonstrates that tissue destruction and bacterial survival/multiplication are dissociated in the bubo and that the primary action of Pla is to protect bacteria from destruction rather than to alter the tissue environment to favor Y. pestis propagation in the host.
The Role of Immune Correlates and Surrogate Markers in the Development of Vaccines and Immunotherapies for Plague  [PDF]
E. D. Williamson
Advances in Preventive Medicine , 2012, DOI: 10.1155/2012/365980
Abstract: One of the difficulties in developing countermeasures to biothreat agents is the challenge inherent in demonstrating their efficacy in man. Since the first publication of the Animal Rule by the FDA, there has been increased discussion of potential correlates of protection in animal models and their use to establish surrogate markers of efficacy in man. The latter need to be relatively easy to measure in assays that are at least qualified, if not validated, in order to derive a quantitative assessment of the clinical benefit conferred. The demonstration of safety and clinical benefit is essential to achieve regulatory approval for countermeasures for which clinical efficacy cannot be tested directly, as is the case for example, for biodefence vaccines. Plague is an ancient, serious infectious disease which is still endemic in regions of the modern world and is a potential biothreat agent. This paper discusses potential immune correlates of protection for plague, from which it may be possible to derive surrogate markers of efficacy, in order to predict the clinical efficacy of candidate prophylaxes and therapies. 1. Plague The ancient disease of plague is still present in endemic regions of the modern world and results in approximately 3,000 reported cases each year [1]. Plague is a flea-vectored infection caused by the Gram-negative bacterium Yersinia pestis, a potential biothreat agent. Originally an enteric pathogen, Y. pestis is thought to have evolved from the enteropathogen Y. pseudotuberculosis [2] as a flea-vectored, enzootic infection. Fleas feed on infected rodents and then transmit bacteria to a susceptible mammal by flea bite. Man is an accidental host in this cycle, but if bitten can contract bubonic plague, a serious infection if not treated promptly before the individual becomes symptomatic. A secondary pneumonic plague can develop in an individual suffering from bubonic plague, and this is of even greater concern, since Y. pestis bacteria are highly transmissible in aerosolised form between unprotected individuals in close contact, with the potential for epidemic spread [3]. 2. Virulence Factors in Yersinia pestis Y. pestis produces a range of antigens and virulence factors, three of which have known protective efficacy as candidate subunit vaccines: F1-antigen [4], V-antigen [5], and Yersinia secretory factor F (YscF) [6]. These three proteins are virulence factors when secreted by Y. pestis during infection. F1 antigen is a capsular protein with antiphagocytic properties [7], whilst the V-antigen is a regulatory protein in the type three
Comparative Genomics of 2009 Seasonal Plague (Yersinia pestis) in New Mexico  [PDF]
Henry S. Gibbons, Michael D. Krepps, Gary Ouellette, Mark Karavis, Lisa Onischuk, Pascale Leonard, Stacey Broomall, Todd Sickler, Janet L. Betters, Paul McGregor, Greg Donarum, Alvin Liem, Ed Fochler, Lauren McNew, C. Nicole Rosenzweig, Evan Skowronski
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031604
Abstract: Plague disease caused by the Gram-negative bacterium Yersinia pestis routinely affects animals and occasionally humans, in the western United States. The strains native to the North American continent are thought to be derived from a single introduction in the late 19th century. The degree to which these isolates have diverged genetically since their introduction is not clear, and new genomic markers to assay the diversity of North American plague are highly desired. To assay genetic diversity of plague isolates within confined geographic areas, draft genome sequences were generated by 454 pyrosequencing from nine environmental and clinical plague isolates. In silico assemblies of Variable Number Tandem Repeat (VNTR) loci were compared to laboratory-generated profiles for seven markers. High-confidence SNPs and small Insertion/Deletions (Indels) were compared to previously sequenced Y. pestis isolates. The resulting panel of mutations allowed clustering of the strains and tracing of the most likely evolutionary trajectory of the plague strains. The sequences also allowed the identification of new putative SNPs that differentiate the 2009 isolates from previously sequenced plague strains and from each other. In addition, new insertion points for the abundant insertion sequences (IS) of Y. pestis are present that allow additional discrimination of strains; several of these new insertions potentially inactivate genes implicated in virulence. These sequences enable whole-genome phylogenetic analysis and allow the unbiased comparison of closely related isolates of a genetically monomorphic pathogen.
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