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B. Joseph Hinnebusch - One of the best experts on this subject based on the ideXlab platform.
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Yersinia pestis subverts the dermal neutrophil response in a mouse model of Bubonic Plague
mBio, 2013Co-Authors: Jeffrey G. Shannon, Aaron M. Hasenkrug, David W. Dorward, Aaron B. Carmody, Vinod Nair, B. Joseph HinnebuschAbstract:The majority of human Yersinia pestis infections result from introduction of bacteria into the skin by the bite of an infected flea. Once in the dermis, Y. pestis can evade the host's innate immune response and subsequently disseminate to the draining lymph node (dLN). There, the pathogen replicates to large numbers, causing the pathognomonic bubo of Bubonic Plague. In this study, several cytometric and microscopic techniques were used to characterize the early host response to intradermal (i.d.) Y. pestis infection. Mice were infected i.d. with fully virulent or attenuated strains of dsRed-expressing Y. pestis, and tissues were analyzed by flow cytometry. By 4 h postinfection, there were large numbers of neutrophils in the infected dermis and the majority of cell-associated bacteria were associated with neutrophils. We observed a significant effect of the virulence plasmid (pCD1) on bacterial survival and neutrophil activation in the dermis. Intravital microscopy of i.d. Y. pestis infection revealed dynamic interactions between recruited neutrophils and bacteria. In contrast, very few bacteria interacted with dendritic cells (DCs), indicating that this cell type may not play a major role early in Y. pestis infection. Experiments using neutrophil depletion and a CCR7 knockout mouse suggest that dissemination of Y. pestis from the dermis to the dLN is not dependent on neutrophils or DCs. Taken together, the results of this study show a very rapid, robust neutrophil response to Y. pestis in the dermis and that the virulence plasmid pCD1 is important for the evasion of this response. IMPORTANCE: Yersinia pestis remains a public health concern today because of sporadic Plague outbreaks that occur throughout the world and the potential for its illegitimate use as a bioterrorism weapon. Since Bubonic Plague pathogenesis is initiated by the introduction of Y. pestis into the skin, we sought to characterize the response of the host's innate immune cells to bacteria early after intradermal infection. We found that neutrophils, innate immune cells that engulf and destroy microbes, are rapidly recruited to the injection site, irrespective of strain virulence, indicating that Y. pestis is unable to subvert neutrophil recruitment to the site of infection. However, we saw a decreased activation of neutrophils that were associated with Y. pestis strains harboring the pCD1 plasmid, which is essential for virulence. These findings indicate a role for pCD1-encoded factors in suppressing the activation/stimulation of these cells in vivo.
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Role of the Yersinia pestis Ail Protein in Preventing a Protective Polymorphonuclear Leukocyte Response during Bubonic Plague
Infection and Immunity, 2011Co-Authors: B. Joseph Hinnebusch, Donald J. Gardner, Clayton O. Jarrett, Julie Callison, Susan K. Buchanan, Gregory V. PlanoAbstract:The ability of Yersinia pestis to forestall the mammalian innate immune response is a fundamental aspect of Plague pathogenesis. In this study, we examined the effect of Ail, a 17-kDa outer membrane protein that protects Y. pestis against complement-mediated lysis, on Bubonic Plague pathogenesis in mice and rats. The Y. pestis ail mutant was attenuated for virulence in both rodent models. The attenuation was greater in rats than in mice, which correlates with the ability of normal rat serum, but not mouse serum, to kill ail-negative Y. pestis in vitro. Intradermal infection with the ail mutant resulted in an atypical, subacute form of Bubonic Plague associated with extensive recruitment of polymorphonuclear leukocytes (PMN or neutrophils) to the site of infection in the draining lymph node and the formation of large purulent abscesses that contained the bacteria. Systemic spread and mortality were greatly attenuated, however, and a productive adaptive immune response was generated after high-dose challenge, as evidenced by high serum antibody levels against Y. pestis F1 antigen. The Y. pestis Ail protein is an important Bubonic Plague virulence factor that inhibits the innate immune response, in particular the recruitment of a protective PMN response to the infected lymph node.
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Transcriptomic and Innate Immune Responses to Yersinia pestis in the Lymph Node during Bubonic Plague
Infection and Immunity, 2010Co-Authors: Jason E. Comer, Aaron B. Carmody, Donald J. Gardner, Daniel E. Sturdevant, Kimmo Virtaneva, Stephen F. Porcella, Dan Long, Rebecca Rosenke, B. Joseph HinnebuschAbstract:A delayed inflammatory response is a prominent feature of infection with Yersinia pestis, the agent of Bubonic and pneumonic Plague. Using a rat model of Bubonic Plague, we examined lymph node histopathology, transcriptome, and extracellular cytokine levels to broadly characterize the kinetics and extent of the host response to Y. pestis and how it is influenced by the Yersinia virulence plasmid (pYV). Remarkably, dissemination and multiplication of wild-type Y. pestis during the Bubonic stage of disease did not induce any detectable gene expression or cytokine response by host lymph node cells in the developing bubo. Only after systemic spread had led to terminal septicemic Plague was a transcriptomic response detected, which included upregulation of several cytokine, chemokine, and other immune response genes. Although an initial intracellular phase of Y. pestis infection has been postulated, a Th1-type cytokine response associated with classical activation of macrophages was not observed during the Bubonic stage of disease. However, elevated levels of interleukin-17 (IL-17) were present in infected lymph nodes. In the absence of pYV, sustained recruitment to the lymph node of polymorphonuclear leukocytes (PMN, or neutrophils), the major IL-17 effector cells, correlated with clearance of infection. Thus, the ability to counteract a PMN response in the lymph node appears to be a major in vivo function of the Y. pestis virulence plasmid.
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The Yersinia pestis caf1M1A1 fimbrial capsule operon promotes transmission by flea bite in a mouse model of Bubonic Plague.
Infection and Immunity, 2008Co-Authors: Florent Sebbane, Donald J. Gardner, Daniel Long, Clayton O. Jarrett, B. Joseph HinnebuschAbstract: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.
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Adaptive response of Yersinia pestis to extracellular effectors of innate immunity during Bubonic Plague
Proceedings of the National Academy of Sciences, 2006Co-Authors: Florent Sebbane, Nadine Lemaître, Daniel E. Sturdevant, Roberto Rebeil, Kimmo Virtaneva, Stephen F. Porcella, B. Joseph HinnebuschAbstract:Yersinia pestis causes Bubonic Plague, characterized by an enlarged, painful lymph node, termed a bubo, that develops after bacterial dissemination from a fleabite site. In susceptible animals, the bacteria rapidly escape containment in the lymph node, spread systemically through the blood, and produce fatal sepsis. The fulminant progression of disease has been largely ascribed to the ability of Y. pestis to avoid phagocytosis and exposure to antimicrobial effectors of innate immunity. In vivo microarray analysis of Y. pestis gene expression, however, revealed an adaptive response to nitric oxide (NO)-derived reactive nitrogen species and to iron limitation in the extracellular environment of the bubo. Polymorphonuclear neutrophils recruited to the infected lymph node expressed abundant inducible NO synthase, and several Y. pestis homologs of genes involved in the protective response to reactive nitrogen species were up-regulated in the bubo. Mutation of one of these genes, which encodes the Hmp flavohemoglobin that detoxifies NO, attenuated virulence. Thus, the ability of Y. pestis to destroy immune cells and remain extracellular in the bubo appears to limit exposure to some but not all innate immune effectors. High NO levels induced during Plague may also influence the developing adaptive immune response and contribute to septic shock.
Florent Sebbane - One of the best experts on this subject based on the ideXlab platform.
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New insights into how Yersinia pestis adapts to its mammalian host during Bubonic Plague.
PLoS Pathogens, 2014Co-Authors: Elizabeth Pradel, Nadine Lemaître, Maud Merchez, Isabelle Ricard, Angéline Reboul, Amélie Dewitte, Florent SebbaneAbstract: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.
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Efficacy of ciprofloxacin-gentamicin combination therapy in murine Bubonic Plague.
PLoS ONE, 2012Co-Authors: Nadine Lemaître, Elizabeth Pradel, Isabelle Ricard, Benoît Foligné, René Courcol, Michel Simonet, Florent SebbaneAbstract: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 post-challenge. 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 log10 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.
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The Yersinia pestis caf1M1A1 fimbrial capsule operon promotes transmission by flea bite in a mouse model of Bubonic Plague.
Infection and Immunity, 2008Co-Authors: Florent Sebbane, Donald J. Gardner, Daniel Long, Clayton O. Jarrett, B. Joseph HinnebuschAbstract: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.
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Adaptive response of Yersinia pestis to extracellular effectors of innate immunity during Bubonic Plague
Proceedings of the National Academy of Sciences, 2006Co-Authors: Florent Sebbane, Nadine Lemaître, Daniel E. Sturdevant, Roberto Rebeil, Kimmo Virtaneva, Stephen F. Porcella, B. Joseph HinnebuschAbstract:Yersinia pestis causes Bubonic Plague, characterized by an enlarged, painful lymph node, termed a bubo, that develops after bacterial dissemination from a fleabite site. In susceptible animals, the bacteria rapidly escape containment in the lymph node, spread systemically through the blood, and produce fatal sepsis. The fulminant progression of disease has been largely ascribed to the ability of Y. pestis to avoid phagocytosis and exposure to antimicrobial effectors of innate immunity. In vivo microarray analysis of Y. pestis gene expression, however, revealed an adaptive response to nitric oxide (NO)-derived reactive nitrogen species and to iron limitation in the extracellular environment of the bubo. Polymorphonuclear neutrophils recruited to the infected lymph node expressed abundant inducible NO synthase, and several Y. pestis homologs of genes involved in the protective response to reactive nitrogen species were up-regulated in the bubo. Mutation of one of these genes, which encodes the Hmp flavohemoglobin that detoxifies NO, attenuated virulence. Thus, the ability of Y. pestis to destroy immune cells and remain extracellular in the bubo appears to limit exposure to some but not all innate immune effectors. High NO levels induced during Plague may also influence the developing adaptive immune response and contribute to septic shock.
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role of the yersinia pestis plasminogen activator in the incidence of distinct septicemic and Bubonic forms of flea borne Plague
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Florent Sebbane, Donald J. Gardner, Daniel Long, Clayton O. Jarrett, Joseph B HinnebuschAbstract:Yersinia pestis is transmitted by fleas and causes Bubonic Plague, characterized by severe local lymphadenitis that progresses rapidly to systemic infection and life-threatening septicemia. Here, we show that although flea-borne transmission usually leads to Bubonic Plague in mice, it can also lead to primary septicemic Plague. However, intradermal injection of Y. pestis, commonly used to mimic transmission by fleabite, leads only to Bubonic Plague. A Y. pestis strain lacking the plasmid-encoded cell-surface plasminogen activator, which is avirulent by intradermal or s.c. injection, was able to cause fatal primary septicemic Plague at low incidence, but not Bubonic Plague, when transmitted by fleas. The results clarify a long-standing uncertainty about the etiology of primary septicemic Plague and support an evolutionary scenario in which Plague first emerged as a flea-borne septicemic disease of limited transmissibility. Subsequent acquisition of the plasminogen activator gene by horizontal transfer enabled the Bubonic form of disease and increased the potential for epidemic spread.
Herbert Tomaso - One of the best experts on this subject based on the ideXlab platform.
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Detection of Yersinia pestis using real-time PCR in patients with suspected Bubonic Plague.
Molecular and Cellular Probes, 2011Co-Authors: Julia M. Riehm, Lila Rahalison, Holger C. Scholz, Martin Pfeffer, Léa Mamiharisoa Razanakoto, Sascha Al Dahouk, Heinrich Neubauer, Bryan Thoma, Herbert TomasoAbstract:Yersinia (Y.) pestis, the causative agent of Plague, is endemic in natural foci of Asia, Africa, and America. Real-time PCR assays have been described as rapid diagnostic tools, but so far none has been validated for its clinical use. In a retrospective clinical study we evaluated three real-time PCR assays in two different assay formats, 5'-nuclease and hybridization probes assays. Lymph node aspirates from 149 patients from Madagascar with the clinical diagnosis of Bubonic Plague were investigated for the detection of Y. pestis DNA. Results of real-time PCR assays targeting the virulence plasmids pPCP1 (pla gene), and pMT1 (caf1, Ymt genes) were compared with an F1-antigen immunochromatographic test (ICT) and cultivation of the organism. Out of the 149 samples an infection with Y. pestis was confirmed by culture in 47 patients while ICT was positive in 88 including all culture proven cases. The best real-time PCR assay was the 5'-nuclease assay targeting pla which was positive in 120 cases. In conclusion, the 5'-nuclease assay targeting pla can be recommended as diagnostic tool for establishing a presumptive diagnosis when Bubonic Plague is clinically suspected.
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Detection of Yersinia pestis using real-time PCR in patients with suspected Bubonic Plague.
Molecular and Cellular Probes, 2011Co-Authors: Julia M. Riehm, L. Rahalison, Holger C. Scholz, Bryan R. Thoma, Martin Pfeffer, Léa Mamiharisoa Razanakoto, Sascha Al Dahouk, Heinrich Neubauer, Herbert TomasoAbstract:Abstract Yersinia (Y.) pestis , the causative agent of Plague, is endemic in natural foci of Asia, Africa, and America. Real-time PCR assays have been described as rapid diagnostic tools, but so far none has been validated for its clinical use. In a retrospective clinical study we evaluated three real-time PCR assays in two different assay formats, 5′-nuclease and hybridization probes assays. Lymph node aspirates from 149 patients from Madagascar with the clinical diagnosis of Bubonic Plague were investigated for the detection of Y. pestis DNA. Results of real-time PCR assays targeting the virulence plasmids pPCP1 ( pla gene), and pMT1 ( caf1 , Ymt genes) were compared with an F1-antigen immunochromatographic test (ICT) and cultivation of the organism. Out of the 149 samples an infection with Y. pestis was confirmed by culture in 47 patients while ICT was positive in 88 including all culture proven cases. The best real-time PCR assay was the 5′-nuclease assay targeting pla which was positive in 120 cases. In conclusion, the 5′-nuclease assay targeting pla can be recommended as diagnostic tool for establishing a presumptive diagnosis when Bubonic Plague is clinically suspected.
Elisabeth Carniel - One of the best experts on this subject based on the ideXlab platform.
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Humoral and cellular immune correlates of protection against Bubonic Plague by a live Yersinia pseudotuberculosis vaccine.
Vaccine, 2019Co-Authors: Christian E. Demeure, Elisabeth Carniel, Anne Derbise, Chloé Guillas, Christiane Gerke, Simon Cauchemez, Javier Pizarro-cerdáAbstract:Abstract Immunization with the live-attenuated Yersinia pseudotuberculosis VTnF1 strain producing a Yersinia pestis F1 pseudocapsule efficiently protects mice against Bubonic and pneumonic Plague. In clinical trials, demonstration of a Plague vaccine’s efficacy in humans will not be feasible, and correlates of protection will be needed to bridge the immune response of protected animals to that of vaccinated humans. Using serum transfer and vaccination of antibody-deficient µMT mice, we established that both humoral and cellular responses elicited by VTnF1 independently conferred protection against Bubonic Plague. Thus, correlates were searched for in both responses, using blood only. Mice were vaccinated with increasing doses of VTnF1 to provide a range of immune responses and survival outcomes. The cellular response was evaluated using an in vitro IFNγ release assay, and IFNγ levels were significantly associated with protection, although some survivors were negative for IFNγ, so that IFNγ release is not a fully satisfactory correlate. Abundant serum IgG against the F1 capsule, Yop injectable toxins, and also non-F1 Y. pestis antigens were found, but none against the LcrV antigen. All readouts correlated to survival and to each other, confirming that vaccination triggered multiple protective mechanisms developing in parallel. Anti-F1 IgG was the most stringent correlate of protection, in both inbred BALB/c mice and outbred OF1 mice. This indicates that antibodies (Ab) to F1 play a dominant role for protection even in the presence of Ab to many other targets. Easy to measure, the anti-F1 IgG titer will be useful to evaluate the immune response in other animal species and in clinical trials.
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Dissociation of Tissue Destruction and Bacterial Expansion during Bubonic Plague.
PLOS Pathogens, 2015Co-Authors: Françoise Guinet, Patrick Ave, Sofia Filali, Christèle Huon, Cyril Savin, Michel Huerre, Laurence Fiette, Elisabeth CarnielAbstract: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.
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Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination.
PLOS Neglected Tropical Diseases, 2015Co-Authors: Anne Derbise, Elisabeth Carniel, Yuri Hanada, Manal Khalifé, Christian E. DemeureAbstract:Background No efficient vaccine against Plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic Plague. This candidate vaccine however failed to confer full protection against Bubonic Plague and did not produce F1 stably. Methodology/Principal Findings The caf operon encoding F1 was inserted into the chromosome of a genetically attenuated Y. pseudotuberculosis, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other Y. pestis antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1—Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (108 CFU) of VTnF1 conferred 100% protection against pneumonic Plague using a high-dose challenge (3,300 LD50) caused by the fully virulent Y. pestis CO92. Moreover, vaccination protected 100% of mice from Bubonic Plague caused by a challenge with 100 LD50 Y. pestis and 93% against a high-dose infection (10,000 LD50). Protection involved fast-acting mechanisms controlling Y. pestis spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving Bubonic and pneumonic Plague respectively, six months after vaccination. Vaccinated mice also survived Bubonic and pneumonic Plague caused by a high-dose of non-encapsulated (F1-) Y. pestis. Significance VTnF1 is an easy-to-produce, genetically stable Plague vaccine candidate, providing a highly efficient and long-lasting protection against both Bubonic and pneumonic Plague caused by wild type or un-encapsulated (F1-negative) Y. pestis. To our knowledge, VTnF1 is the only Plague vaccine ever reported that could provide high and durable protection against the two forms of Plague after a single oral administration.
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Imaging of Bubonic Plague dynamics by in vivo tracking of bioluminescent Yersinia pestis.
PLoS ONE, 2012Co-Authors: Toan Nham, Sofia Filali, Anne Derbise, Camille Danne, Elisabeth CarnielAbstract:Yersinia pestis dissemination in a host is usually studied by enumerating bacteria in the tissues of animals sacrificed at different times. This laborious methodology gives only snapshots of the infection, as the infectious process is not synchronized. In this work we used in vivo bioluminescence imaging (BLI) to follow Y. pestis dissemination during Bubonic Plague. We first demonstrated that Y. pestis CO92 transformed with pGEN-luxCDABE stably emitted bioluminescence in vitro and in vivo, while retaining full virulence. The light produced from live animals allowed to delineate the infected organs and correlated with bacterial loads, thus validating the BLI tool. We then showed that the first step of the infectious process is a bacterial multiplication at the injection site (linea alba), followed by a colonization of the draining inguinal lymph node(s), and subsequently of the ipsilateral axillary lymph node through a direct connection between the two nodes. A mild bacteremia and an effective filtering of the blood stream by the liver and spleen probably accounted for the early bacterial blood clearance and the simultaneous development of bacterial foci within these organs. The saturation of the filtering capacity of the spleen and liver subsequently led to terminal septicemia. Our results also indicate that secondary lymphoid tissues are the main targets of Y. pestis multiplication and that colonization of other organs occurs essentially at the terminal phase of the disease. Finally, our analysis reveals that the high variability in the kinetics of infection is attributable to the time the bacteria remain confined at the injection site. However, once Y. pestis has reached the draining lymph nodes, the disease progresses extremely rapidly, leading to the invasion of the entire body within two days and to death of the animals. This highlights the extraordinary capacity of Y. pestis to annihilate the host innate immune response.
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Oral vaccination against Bubonic Plague using a live avirulent Yersinia pseudotuberculosis strain.
Infection and Immunity, 2008Co-Authors: Thierry Blisnick, Patrick Ave, Michel Huerre, Elisabeth Carniel, Christian E. DemeureAbstract:We evaluated the possibility of using Yersinia pseudotuberculosis as a live vaccine against Plague because it shares high genetic identity with Y. pestis while being much less virulent, genetically much more stable, and deliverable orally. A total of 41 Y. pseudotuberculosis strains were screened by PCR for the absence of the high pathogenicity island, the superantigens YPM, and the type IV pilus and the presence of the pYV virulence plasmid. One strain (IP32680) fulfilled these criteria. This strain was avirulent in mice upon intragastric or subcutaneous inoculation and persisted for 2 months in the mouse intestine without clinical signs of disease. IP32680 reached the mesenteric lymph nodes, spleen, and liver without causing major histological lesions and was cleared after 13 days. The antibodies produced in vaccinated animals recognized both Y. pseudotuberculosis and Y. pestis antigens efficiently. After a subcutaneous challenge with Y. pestis CO92, bacteria were found in low amounts in the organs and rarely in the blood of vaccinated animals. One oral IP32680 inoculation protected 75% of the mice, and two inoculations induced much higher antibody titers and protected 88% of the mice. Our results thus validate the concept that an attenuated Y. pseudotuberculosis strain can be an efficient, inexpensive, safe, and easy-to-produce live vaccine for oral immunization against Bubonic Plague.
Joseph B Hinnebusch - One of the best experts on this subject based on the ideXlab platform.
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antibody opsonization enhances early interactions between yersinia pestis and neutrophils in the skin and draining lymph node in a mouse model of Bubonic Plague
Infection and Immunity, 2020Co-Authors: Jeffrey G. Shannon, Joseph B HinnebuschAbstract:Bubonic Plague results when Yersinia pestis is deposited in the skin via the bite of an infected flea. Bacteria then traffic to the draining lymph node (dLN) where they replicate to large numbers. Without treatment, this infection can result in a highly fatal septicemia. Several Plague vaccine candidates are currently at various stages of development, but no licensed vaccine is available in the United States. Though polyclonal and monoclonal antibodies (Ab) can provide complete protection against Bubonic Plague in animal models, the mechanisms responsible for this antibody-mediated immunity (AMI) to Y. pestis remain poorly understood. Here we examine the effects of Ab opsonization on Y. pestis interactions with phagocytes in vitro and in vivo Opsonization of Y. pestis with polyclonal antiserum modestly increased phagocytosis/killing by and oxidative burst of murine neutrophils in vitro Intravital microscopy (IVM) showed increased association of Ab opsonized Y. pestis with neutrophils in the dermis in a mouse model of Bubonic Plague. IVM of popliteal LNs after i.d. injection of bacteria in the footpad revealed increased Y. pestis-neutrophil interactions and increased neutrophil crawling and extravasation in response to Ab-opsonized bacteria. Thus, despite only having a modest effect in in vitro assays, opsonizing Ab had a dramatic effect in vivo on Y. pestis-neutrophil interactions in the dermis and dLN very early after infection. These data shed new light on the importance of neutrophils in AMI to Y. pestis and may provide a new correlate of protection for evaluation of Plague vaccine candidates.
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role of the yersinia pestis plasminogen activator in the incidence of distinct septicemic and Bubonic forms of flea borne Plague
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Florent Sebbane, Donald J. Gardner, Daniel Long, Clayton O. Jarrett, Joseph B HinnebuschAbstract:Yersinia pestis is transmitted by fleas and causes Bubonic Plague, characterized by severe local lymphadenitis that progresses rapidly to systemic infection and life-threatening septicemia. Here, we show that although flea-borne transmission usually leads to Bubonic Plague in mice, it can also lead to primary septicemic Plague. However, intradermal injection of Y. pestis, commonly used to mimic transmission by fleabite, leads only to Bubonic Plague. A Y. pestis strain lacking the plasmid-encoded cell-surface plasminogen activator, which is avirulent by intradermal or s.c. injection, was able to cause fatal primary septicemic Plague at low incidence, but not Bubonic Plague, when transmitted by fleas. The results clarify a long-standing uncertainty about the etiology of primary septicemic Plague and support an evolutionary scenario in which Plague first emerged as a flea-borne septicemic disease of limited transmissibility. Subsequent acquisition of the plasminogen activator gene by horizontal transfer enabled the Bubonic form of disease and increased the potential for epidemic spread.
