The Experts below are selected from a list of 111 Experts worldwide ranked by ideXlab platform
Deborah M Anderson - One of the best experts on this subject based on the ideXlab platform.
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shift from primary pneumonic to secondary Septicemic Plague by decreasing the volume of intranasal challenge with yersinia pestis in the murine model
PLOS ONE, 2019Co-Authors: Rachel M Olson, Deborah M AndersonAbstract:Yersinia pestis is the causative agent of pneumonic Plague, a disease involving uncontrolled bacterial growth and host immunopathology. Secondary Septicemic Plague commonly occurs as a consequence of the host inflammatory response that causes vasodilation and vascular leakage, which facilitates systemic spread of the bacteria and the colonization of secondary tissues. The mortality rates of pneumonic and Septicemic Plague are high even when antibiotics are administered. In this work, we show that primary pneumonic or secondary Septicemic Plague can be preferentially modeled in mice by varying the volume used for intranasal delivery of Y. pestis. Low volume intranasal challenge (10μL) of wild type Y. pestis resulted in a high frequency of lethal secondary Septicemic Plague, with a low degree of primary lung infection and rapid development of sepsis. In contrast, high volume intranasal challenge (30μL) yielded uniform early lung infection and primary disease and a significant increase in lethality. In a commonly used BSL2 model, high volume challenge with Y. pestis lacking the pigmentation locus (pgm-) gave 105-fold greater deposition compared to low volume challenge, yet moribund mice did not develop severe lung disease and there was no detectable difference in lethality. These data indicate the primary cause of death of mice in the BSL2 model is sepsis regardless of intranasal dosing method. Overall, these findings allow for the preferential modeling of pneumonic or Septicemic Plague by intranasal dosing of mice with Y. pestis.
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Frequency of Septicemic Plague in the absence of primary pneumonia increases with decreasing dosing volume.
2019Co-Authors: Rachel M Olson, Deborah M AndersonAbstract:Representative lesions from mice challenged with 2,000 CFU of wild type Y. pestis in Fig 1 that succumbed to disease on day 4. Formalin fixed tissues collected at necropsy were sectioned and stained with hematoxylin and eosin (H&E). (A) 30μL group; (B-C) 20μL group, high (B) and low (C) severity scores in the lungs; (D) 10μL group. Scale bar represents 100μm (liver) or 200μm (lungs and spleen).
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Novel Genetic Tools for Diaminopimelic Acid Selection in Virulence Studies of Yersinia pestis
2013Co-Authors: Nicholas A Eisele, Paul E Anderson, Lauren L. Keleher, Deborah M AndersonAbstract:Molecular studies of bacterial virulence are enhanced by expression of recombinant DNA during infection to allow complementation of mutants and expression of reporter proteins in vivo. For highly pathogenic bacteria, such as Yersinia pestis, these studies are currently limited because deliberate introduction of antibiotic resistance is restricted to those few which are not human treatment options. In this work, we report the development of alternatives to antibiotics as tools for host-pathogen research during Yersinia pestis infections focusing on the diaminopimelic acid (DAP) pathway, a requirement for cell wall synthesis in eubacteria. We generated a mutation in the dapA-nlpB(dapX) operon of Yersinia pestis KIM D27 and CO92 which eliminated the expression of both genes. The resulting strains were auxotrophic for diaminopimelic acid and this phenotype was complemented in trans by expressing dapA in single and multi-copy. In vivo, we found that plasmids derived from the p15a replicon were cured without selection, while selection for DAP enhanced stability without detectable loss of any of the three resident virulence plasmids. The dapAX mutation rendered Y. pestis avirulent in mouse models of bubonic and Septicemic Plague which could be complemented when dapAX was inserted in single or multi-copy, restoring development of disease that was indistinguishable from the wild type parent strain. We further identified a high level, constitutive promoter in Y. pestis that could be used to drive expression of fluorescent reporters in dapAX strains that had minimal impact to virulence in mouse models while enabling sensitive detection of bacteria during infection. Thus
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Opposing roles for interferon regulatory factor-3 (IRF-3) and type I interferon signaling during Plague
2012Co-Authors: Ami A. Patel, Hanni Lee-lewis, Jennifer Hughes-hanks, Craig A. Lewis, Deborah M AndersonAbstract:Type I interferons (IFN-I) broadly control innate immunity and are typically transcriptionally induced by Interferon Regulatory Factors (IRFs) following stimulation of pattern recognition receptors within the cytosol of host cells. For bacterial infection, IFN-I signaling can result in widely variant responses, in some cases contributing to the pathogenesis of disease while in others contributing to host defense. In this work, we addressed the role of type I IFN during Yersinia pestis infection in a murine model of Septicemic Plague. Transcription of IFN-b was induced in vitro and in vivo and contributed to pathogenesis. Mice lacking the IFN-I receptor, Ifnar, were less sensitive to disease and harbored more neutrophils in the later stage of infection which correlated with protection from lethality. In contrast, IRF-3, a transcription factor commonly involved in inducing IFN-b following bacterial infection, was not necessary for IFN production but instead contributed to host defense. In vitro, phagocytosis of Y. pestis by macrophages and neutrophils was more effective in the presence of IRF-3 and was not affected by IFN-b signaling. This activity correlated with limited bacterial growth in vivo in the presence of IRF-3. Together the data demonstrate that IRF-3 is able to activate pathways of innate immunity against bacterial infection that extend beyond regulation of IFN-b production
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novel genetic tools for diaminopimelic acid selection in virulence studies of yersinia pestis
PLOS ONE, 2011Co-Authors: David M Bland, Nicholas A Eisele, Paul E Anderson, Lauren L. Keleher, Deborah M AndersonAbstract:Molecular studies of bacterial virulence are enhanced by expression of recombinant DNA during infection to allow complementation of mutants and expression of reporter proteins in vivo. For highly pathogenic bacteria, such as Yersinia pestis, these studies are currently limited because deliberate introduction of antibiotic resistance is restricted to those few which are not human treatment options. In this work, we report the development of alternatives to antibiotics as tools for host-pathogen research during Yersinia pestis infections focusing on the diaminopimelic acid (DAP) pathway, a requirement for cell wall synthesis in eubacteria. We generated a mutation in the dapA-nlpB(dapX) operon of Yersinia pestis KIM D27 and CO92 which eliminated the expression of both genes. The resulting strains were auxotrophic for diaminopimelic acid and this phenotype was complemented in trans by expressing dapA in single and multi-copy. In vivo, we found that plasmids derived from the p15a replicon were cured without selection, while selection for DAP enhanced stability without detectable loss of any of the three resident virulence plasmids. The dapAX mutation rendered Y. pestis avirulent in mouse models of bubonic and Septicemic Plague which could be complemented when dapAX was inserted in single or multi-copy, restoring development of disease that was indistinguishable from the wild type parent strain. We further identified a high level, constitutive promoter in Y. pestis that could be used to drive expression of fluorescent reporters in dapAX strains that had minimal impact to virulence in mouse models while enabling sensitive detection of bacteria during infection. Thus, diaminopimelic acid selection for single or multi-copy genetic systems in Yersinia pestis offers an improved alternative to antibiotics for in vivo studies that causes minimal disruption to virulence.
B. Joseph Hinnebusch - One of the best experts on this subject based on the ideXlab platform.
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Comparison of the transmission efficiency and Plague progression dynamics associated with two mechanisms by which fleas transmit Yersinia pestis.
PLoS pathogens, 2020Co-Authors: Christopher F Bosio, Dana P. Scott, Jonathan Fintzi, B. Joseph HinnebuschAbstract:Yersinia pestis can be transmitted by fleas during the first week after an infectious blood meal, termed early-phase or mass transmission, and again after Y. pestis forms a cohesive biofilm in the flea foregut that blocks normal blood feeding. We compared the transmission efficiency and the progression of infection after transmission by Oropsylla montana fleas at both stages. Fleas were allowed to feed on mice three days after an infectious blood meal to evaluate early-phase transmission, or after they had developed complete proventricular blockage. Transmission was variable and rather inefficient by both modes, and the odds of early-phase transmission was positively associated with the number of infected fleas that fed. Disease progression in individual mice bitten by fleas infected with a bioluminescent strain of Y. pestis was tracked. An early prominent focus of infection at the intradermal flea bite site and dissemination to the draining lymph node(s) soon thereafter were common features, but unlike what has been observed in intradermal injection models, this did not invariably lead to further systemic spread and terminal disease. Several of these mice resolved the infection without progression to terminal sepsis and developed an immune response to Y. pestis, particularly those that received an intermediate number of early-phase flea bites. Furthermore, two distinct types of terminal disease were noted: the stereotypical rapid onset terminal disease within four days, or a prolonged onset preceded by an extended, fluctuating infection of the lymph nodes before eventual systemic dissemination. For both modes of transmission, bubonic Plague rather than primary Septicemic Plague was the predominant disease outcome. The results will help to inform mathematical models of flea-borne Plague dynamics used to predict the relative contribution of the two transmission modes to epizootic outbreaks that erupt periodically from the normal enzootic background state.
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Role of the Yersinia pestis yersiniabactin iron acquisition system in the incidence of flea-borne Plague.
PloS one, 2010Co-Authors: Florent Sebbane, Donald J. Gardner, Daniel Long, Clayton O. Jarrett, B. Joseph HinnebuschAbstract: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.
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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.
Donald J. Gardner - One of the best experts on this subject based on the ideXlab platform.
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Role of the Yersinia pestis yersiniabactin iron acquisition system in the incidence of flea-borne Plague.
PloS one, 2010Co-Authors: Florent Sebbane, Donald J. Gardner, Daniel Long, Clayton O. Jarrett, B. Joseph HinnebuschAbstract: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.
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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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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, 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.
Nicholas A Eisele - One of the best experts on this subject based on the ideXlab platform.
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Novel Genetic Tools for Diaminopimelic Acid Selection in Virulence Studies of Yersinia pestis
2013Co-Authors: Nicholas A Eisele, Paul E Anderson, Lauren L. Keleher, Deborah M AndersonAbstract:Molecular studies of bacterial virulence are enhanced by expression of recombinant DNA during infection to allow complementation of mutants and expression of reporter proteins in vivo. For highly pathogenic bacteria, such as Yersinia pestis, these studies are currently limited because deliberate introduction of antibiotic resistance is restricted to those few which are not human treatment options. In this work, we report the development of alternatives to antibiotics as tools for host-pathogen research during Yersinia pestis infections focusing on the diaminopimelic acid (DAP) pathway, a requirement for cell wall synthesis in eubacteria. We generated a mutation in the dapA-nlpB(dapX) operon of Yersinia pestis KIM D27 and CO92 which eliminated the expression of both genes. The resulting strains were auxotrophic for diaminopimelic acid and this phenotype was complemented in trans by expressing dapA in single and multi-copy. In vivo, we found that plasmids derived from the p15a replicon were cured without selection, while selection for DAP enhanced stability without detectable loss of any of the three resident virulence plasmids. The dapAX mutation rendered Y. pestis avirulent in mouse models of bubonic and Septicemic Plague which could be complemented when dapAX was inserted in single or multi-copy, restoring development of disease that was indistinguishable from the wild type parent strain. We further identified a high level, constitutive promoter in Y. pestis that could be used to drive expression of fluorescent reporters in dapAX strains that had minimal impact to virulence in mouse models while enabling sensitive detection of bacteria during infection. Thus
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novel genetic tools for diaminopimelic acid selection in virulence studies of yersinia pestis
PLOS ONE, 2011Co-Authors: David M Bland, Nicholas A Eisele, Paul E Anderson, Lauren L. Keleher, Deborah M AndersonAbstract:Molecular studies of bacterial virulence are enhanced by expression of recombinant DNA during infection to allow complementation of mutants and expression of reporter proteins in vivo. For highly pathogenic bacteria, such as Yersinia pestis, these studies are currently limited because deliberate introduction of antibiotic resistance is restricted to those few which are not human treatment options. In this work, we report the development of alternatives to antibiotics as tools for host-pathogen research during Yersinia pestis infections focusing on the diaminopimelic acid (DAP) pathway, a requirement for cell wall synthesis in eubacteria. We generated a mutation in the dapA-nlpB(dapX) operon of Yersinia pestis KIM D27 and CO92 which eliminated the expression of both genes. The resulting strains were auxotrophic for diaminopimelic acid and this phenotype was complemented in trans by expressing dapA in single and multi-copy. In vivo, we found that plasmids derived from the p15a replicon were cured without selection, while selection for DAP enhanced stability without detectable loss of any of the three resident virulence plasmids. The dapAX mutation rendered Y. pestis avirulent in mouse models of bubonic and Septicemic Plague which could be complemented when dapAX was inserted in single or multi-copy, restoring development of disease that was indistinguishable from the wild type parent strain. We further identified a high level, constitutive promoter in Y. pestis that could be used to drive expression of fluorescent reporters in dapAX strains that had minimal impact to virulence in mouse models while enabling sensitive detection of bacteria during infection. Thus, diaminopimelic acid selection for single or multi-copy genetic systems in Yersinia pestis offers an improved alternative to antibiotics for in vivo studies that causes minimal disruption to virulence.
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Chemokine Receptor CXCR2 Mediates Bacterial Clearance Rather Than Neutrophil Recruitment in a Murine Model of Pneumonic Plague
The American journal of pathology, 2011Co-Authors: Nicholas A Eisele, Charles R Brown, Hanni Lee-lewis, Cynthia Besch-williford, Deborah M AndersonAbstract:Pulmonary infection by Yersinia pestis causes pneumonic Plague, a necrotic bronchopneumonia that is rapidly lethal and highly contagious. Acute pneumonic Plague accompanies the up-regulation of pro-inflammatory cytokines and chemokines, suggesting that the host innate immune response may contribute to the development of disease. To address this possibility, we sought to understand the consequences of neutrophil recruitment during pneumonic Plague, and we studied the susceptibility of C3H-HeN mice lacking the CXC chemokine KC or its receptor CXC receptor 2 (CXCR2) to pulmonary Y. pestis infection. We found that without Kc or Cxcr2, disease progression was accelerated both in bacterial growth and development of primary bronchopneumonia. When examined in an antibody clearance model, Cxcr2−/− mice were not protected by neutralizing Y. pestis antibodies, yet bacterial growth in the lungs was delayed in a manner associated with a neutrophil-mediated inflammatory response. After this initial delay, however, robust neutrophil recruitment in Cxcr2−/− mice correlated with bacterial growth and the development of fulminant pneumonic and Septicemic Plague. In contrast, attenuated Y. pestis lacking the conserved pigmentation locus could be cleared from the lungs in the absence of Cxcr2 indicating virulence factors within this locus may inhibit CXCR2-independent pathways of bacterial killing. Together, the data suggest CXCR2 uniquely induces host defense mechanisms that are effective against virulent Y. pestis, raising new insight into the activation of neutrophils during infection.
Florent Sebbane - One of the best experts on this subject based on the ideXlab platform.
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Disease outcome in mice bitten by fleas infected with wild-type or irp2 Y. pestis.
2013Co-Authors: Florent Sebbane, Daniel Long, Clayton Jarrett, Donald Gardner, Joseph B HinnebuschAbstract:*Cumulative number of bites from blocked fleas.†B and a/B, typical and atypical bubonic Plague respectively; S, primary Septicemic Plague; -, no disease.
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Role of the Yersinia pestis yersiniabactin iron acquisition system in the incidence of flea-borne Plague.
PloS one, 2010Co-Authors: Florent Sebbane, Donald J. Gardner, Daniel Long, Clayton O. Jarrett, B. Joseph HinnebuschAbstract: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.
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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, 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.
