The Experts below are selected from a list of 8313 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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modification of the pulmonary myd88 inflammatory response underlies the role of the yersinia pestis pigmentation locus in primary Pneumonic Plague
Infection and Immunity, 2021Co-Authors: Rachel M Olson, Miqdad O Dhariwala, William J Mitchell, Jerod A Skyberg, Deborah M. AndersonAbstract:Pneumonic Plague, caused by Yersinia pestis, is a rapidly progressing bronchopneumonia involving focal bacterial growth, neutrophilic congestion, and alveolar necrosis. Within a short time after inhalation of Y. pestis, inflammatory cytokines are expressed via the Toll/IL1 adaptor myeloid differentiation primary response 88 (MyD88), which facilitates the primary lung infection. We previously showed that Y. pestis lacking the 102kb chromosomal pigmentation locus (pgm) are unable to cause inflammatory damage in the lungs, whereas the WT strain induces the toxic MyD88 pulmonary inflammatory response. In this work, we investigated the involvement of the pgm in skewing the inflammatory response during Pneumonic Plague. We show that the early MyD88-dependent and -independent cytokine responses to pgm- Y. pestis infection of the lungs are similar yet distinct from those that occur during pgm+ infection. Furthermore, we found that MyD88 was necessary to prevent growth of the iron-starved pgm- Y. pestis despite the presence of iron chelators lactoferrin and transferrin. However, while this induced neutrophil recruitment, there was no hyper-inflammatory response and pulmonary disease was mild without MyD88. In contrast, growth in blood and tissues progressed rapidly in the absence of MyD88, due to an almost total loss of serum IFNγ. We further show that the expression of MyD88 by myeloid cells is important to control bacteremia, but not the primary lung infection. The combined data indicate distinct roles for myeloid and non-myeloid MyD88, and suggest that expression of the pgm locus is necessary to skew the inflammatory response in the lungs to cause Pneumonic Plague.
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activation of heme oxygenase expression by cobalt protoporphyrin treatment prevents Pneumonic Plague caused by inhalation of yersinia pestis
Antimicrobial Agents and Chemotherapy, 2020Co-Authors: Joshua L Willix, Rachel M Olson, Paul E. Anderson, Jacob L Stockton, Deborah M. AndersonAbstract:Pneumonic Plague, caused by the Gram-negative bacteria Yersinia pestis, is an invasive, rapidly progressing disease with poor survival rates. Following inhalation of Y. pestis, bacterial invasion of the lungs and a tissue-damaging inflammatory response allows vascular spread of the infection. Consequently, primary Pneumonic Plague is a multiorgan disease involving sepsis and necrosis of immune tissues and the liver, as well as bronchopneumonia and rampant bacterial growth. Given the likely role of the hyperinflammatory response in accelerating the destruction of tissue, in this work we evaluated the therapeutic potential of the inducible cytoprotective enzyme heme oxygenase 1 (HO-1) against primary Pneumonic Plague. On its own, the HO-1 inducer cobalt protoporphyrin IX (CoPP) provided mice protection from lethal challenge with Y. pestis CO92 with improved pulmonary bacterial clearance and a dampened inflammatory response compared to vehicle-treated mice. Furthermore, CoPP treatment combined with doxycycline strongly enhanced protection in a rat aerosol challenge model. Compared to doxycycline alone, CoPP treatment increased survival, with a 3-log decrease in median bacterial titer recovered from the lungs and the general absence of a systemic hyperinflammatory response. In contrast, treatment with the HO-1 inhibitor SnPP had no detectable impact on doxycycline efficacy. The combined data indicate that countering inflammatory toxicity by therapeutically inducing HO-1 is effective in reducing the rampant growth of Y. pestis and preventing Pneumonic Plague.
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standardized method for aerosol challenge of rodents with yersinia pestis for modeling primary Pneumonic Plague
Methods of Molecular Biology, 2019Co-Authors: Paul E. Anderson, Rachel M Olson, Joshua L Willix, Deborah M. AndersonAbstract:Primary Pneumonic Plague occurs when Yersinia pestis is inhaled into the lower respiratory tract where it invades the alveoli and grows. Rapid bacterial growth eventually elicits a neutrophilic inflammatory response that is ineffective and damaging, leading to accelerated progression of disease. In the laboratory, modeling of primary Pneumonic Plague can be accomplished by instillation of bacterial culture in the nares of anesthetized mice and rats. Although primary Pneumonic Plague can develop from this method, variability in dosing and side effects of anesthesia can complicate data interpretation. In contrast, aerosol challenge models allow for well-controlled studies of Pneumonic Plague with minimal experimental bias and unwanted side effects. For these reasons, antibiotic testing and the licensing of new treatments depend on efficacy data generated from aerosol delivery of Y. pestis in order to more accurately model transmission and the early stages of human Pneumonic Plague. In order to meet this need, we have extensively characterized Pneumonic Plague in mice and rats challenged by nose-only exposure to Yersinia pestis. With this approach, simultaneous challenge of large cohorts of animals, gently restrained and not anesthetized, assures safe, well-controlled, unbiased, and uniform infection. In this chapter, we present a standardized method for reproducible aerosol delivery of wild-type Y. pestis to rodents for experimental models of primary Pneumonic Plague.
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Remote monitoring of the progression of primary Pneumonic Plague in Brown Norway rats in high-capacity, high-containment housing.
Pathogens and disease, 2014Co-Authors: Eric A. Coate, Andrew G. Kocsis, Kristen N. Peters, Paul E. Anderson, Mark R. Ellersieck, Deborah M. Fine, Deborah M. AndersonAbstract:Development of new vaccines, diagnostics, and therapeutics for biodefense or other relatively rare infectious diseases is hindered by the lack of naturally occurring human disease on which to conduct clinical trials of efficacy. To overcome this experimental gap, the U.S. Food and Drug Administration established the Animal Rule, in which efficacy testing in two well-characterized animal models that closely resemble human disease may be accepted in lieu of large-scale clinical trials for diseases with limited natural human incidence. In this report, we evaluated the Brown Norway rat as a model for Pneumonic Plague and describe the natural history of clinical disease following inhalation exposure to Yersinia pestis. In high-capacity, high-containment housing, we monitored temperature, activity, heart rate, and rhythm by capturing electronic impulses transmitted from abdominal telemeter implants. Using this system, we show that reduced activity and development of fever are sensitive indications of disease progression. Furthermore, we identified heart arrhythmias as contributing factors to the rapid progression to lethality following the fever response. Together, these data validate the Brown Norway rat as an experimental model for human Pneumonic Plague and provide new insight that may ultimately lead to novel approaches in postexposure treatment of this devastating infection.
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early apoptosis of macrophages modulated by injection of yersinia pestis yopk promotes progression of primary Pneumonic Plague
PLOS Pathogens, 2013Co-Authors: Kristen N. Peters, Charles R Brown, Miqdad O Dhariwala, Jennifer Hughes M Hanks, Deborah M. AndersonAbstract:Yersinia pestis causes Pneumonic Plague, a disease characterized by inflammation, necrosis and rapid bacterial growth which together cause acute lung congestion and lethality. The bacterial type III secretion system (T3SS) injects 7 effector proteins into host cells and their combined activities are necessary to establish infection. Y. pestis infection of the lungs proceeds as a biphasic inflammatory response believed to be regulated through the control of apoptosis and pyroptosis by a single, well-conserved T3SS effector protein YopJ. Recently, YopJ-mediated pyroptosis, which proceeds via the NLRP3-inflammasome, was shown to be regulated by a second T3SS effector protein YopK in the related strain Y. pseudotuberculosis. In this work, we show that for Y. pestis, YopK appears to regulate YopJ-mediated apoptosis, rather than pyroptosis, of macrophages. Inhibition of caspase-8 blocked YopK-dependent apoptosis, suggesting the involvement of the extrinsic pathway, and appeared cell-type specific. However, in contrast to yopJ, deletion of yopK caused a large decrease in virulence in a mouse Pneumonic Plague model. YopK-dependent modulation of macrophage apoptosis was observed at 6 and 24 hours post-infection (HPI). When YopK was absent, decreased populations of macrophages and dendritic cells were seen in the lungs at 24 HPI and correlated with resolution rather than progression of inflammation. Together the data suggest that Y. pestis YopK may coordinate the inflammatory response during Pneumonic Plague through the regulation of apoptosis of immune cells.
William E Goldman - One of the best experts on this subject based on the ideXlab platform.
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the yersinia pestis gtpase bipa promotes pathogenesis of primary Pneumonic Plague
Infection and Immunity, 2021Co-Authors: Samantha D Crane, William E Goldman, Srijon Kaushik Banerjee, Kara R Eichelberger, Richard C Kurten, Roger D PechousAbstract:ABSTRACT Yersinia pestis is a highly virulent pathogen and the causative agent of bubonic, septicemic, and Pneumonic Plague. Primary Pneumonic Plague caused by inhalation of respiratory droplets contaminated with Y. pestis is nearly 100% lethal within 4 to 7 days without antibiotic intervention. Pneumonic Plague progresses in two phases, beginning with extensive bacterial replication in the lung with minimal host responsiveness, followed by the abrupt onset of a lethal proinflammatory response. The precise mechanisms by which Y. pestis is able to colonize the lung and survive two very distinct disease phases remain largely unknown. To date, a few bacterial virulence factors, including the Ysc type 3 secretion system, are known to contribute to the pathogenesis of primary Pneumonic Plague. The bacterial GTPase BipA has been shown to regulate expression of virulence factors in a number of Gram-negative bacteria, including Pseudomonas aeruginosa, Escherichia coli, and Salmonella enterica serovar Typhi. However, the role of BipA in Y. pestis has yet to be investigated. Here, we show that BipA is a Y. pestis virulence factor that promotes defense against early neutrophil-mediated bacterial killing in the lung. This work identifies a novel Y. pestis virulence factor and highlights the importance of early bacterial/neutrophil interactions in the lung during primary Pneumonic Plague.
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tn seq analysis identifies genes important for yersinia pestis adherence during primary Pneumonic Plague
mSphere, 2020Co-Authors: Kara R Eichelberger, Victoria E Sepulveda, John Ford, Sara R Selitsky, Piotr A Mieczkowski, Joel S Parker, William E GoldmanAbstract:ABSTRACT Following inhalation, Yersinia pestis rapidly colonizes the lung to establish infection during primary Pneumonic Plague. Although several adhesins have been identified in Yersinia spp., the factors mediating early Y. pestis adherence in the lung remain unknown. To identify genes important for Y. pestis adherence during primary Pneumonic Plague, we used transposon insertion sequencing (Tn-seq). Wild-type and capsule mutant (Δcaf1) Y. pestis transposon mutant libraries were serially passaged in vivo to enrich for nonadherent mutants in the lung using a mouse model of primary Pneumonic Plague. Sequencing of the passaged libraries revealed six mutants that were significantly enriched in both the wild-type and Δcaf1Y. pestis backgrounds. The enriched mutants had insertions in genes that encode transcriptional regulators, chaperones, an endoribonuclease, and YPO3903, a hypothetical protein. Using single-strain infections and a transcriptional analysis, we identified a significant role for YPO3903 in Y. pestis adherence in the lung and showed that YPO3903 regulated transcript levels of psaA, which encodes a fimbria previously implicated in Y. pestis adherence in vitro. Deletion of psaA had a minor effect on Y. pestis adherence in the lung, suggesting that YPO3903 regulates other adhesins in addition to psaA. By enriching for mutations in genes that regulate the expression or assembly of multiple genes or proteins, we obtained screen results indicating that there may be not just one dominant adhesin but rather several factors that contribute to early Y. pestis adherence during primary Pneumonic Plague. IMPORTANCE Colonization of the lung by Yersinia pestis is a critical first step in establishing infection during primary Pneumonic Plague, a disease characterized by high lethality. However, the mechanisms by which Y. pestis adheres in the lung after inhalation remain elusive. Here, we used Tn-seq to identify Y. pestis genes important for adherence early during primary Pneumonic Plague. Our mutant enrichment strategy resulted in the identification of genes important for regulation and assembly of genes and proteins rather than adhesin genes themselves. These results reveal that there may be multiple Y. pestis adhesins or redundancy among adhesins. Identifying the adhesins regulated by the genes identified in our enrichment screen may reveal novel therapeutic targets for preventing Y. pestis adherence and the subsequent development of Pneumonic Plague.
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Pneumonic Plague the darker side of yersinia pestis
Trends in Microbiology, 2016Co-Authors: Roger D Pechous, Vijay Sivaraman, Nikolas M Stasulli, William E GoldmanAbstract:Inhalation of the bacterium Yersinia pestis results in primary Pneumonic Plague. Pneumonic Plague is the most severe manifestation of Plague, with mortality rates approaching 100% in the absence of treatment. Its rapid disease progression, lethality, and ability to be transmitted via aerosol have compounded fears of the intentional release of Y. pestis as a biological weapon. Importantly, recent epidemics of Plague have highlighted a significant role for Pneumonic Plague during outbreaks of Y. pestis infections. In this review we describe the characteristics of Pneumonic Plague, focusing on its disease progression and pathogenesis. The rapid time-course, severity, and difficulty of treating Pneumonic Plague highlight how differences in the route of disease transmission can enhance the lethality of an already deadly pathogen.
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spatially distinct neutrophil responses within the inflammatory lesions of Pneumonic Plague
Mbio, 2015Co-Authors: Nikolas M Stasulli, Roger D Pechous, Paul A Price, Kara R Eichelberger, Joel S Parker, Stephanie A Montgomery, William E GoldmanAbstract:ABSTRACT During Pneumonic Plague, the bacterium Yersinia pestis elicits the development of inflammatory lung lesions that continue to expand throughout infection. This lesion development and persistence are poorly understood. Here, we examine spatially distinct regions of lung lesions using laser capture microdissection and transcriptome sequencing (RNA-seq) analysis to identify transcriptional differences between lesion microenvironments. We show that cellular pathways involved in leukocyte migration and apoptosis are downregulated in the center of lung lesions compared to the periphery. Probing for the bacterial factor(s) important for the alteration in neutrophil survival, we show both in vitro and in vivo that Y. pestis increases neutrophil survival in a manner that is dependent on the type III secretion system effector YopM. This research explores the complexity of spatially distinct host-microbe interactions and emphasizes the importance of cell relevance in assays in order to fully understand Y. pestis virulence. IMPORTANCE Yersinia pestis is a high-priority pathogen and continues to cause outbreaks worldwide. The ability of Y. pestis to be transmitted via respiratory droplets and its history of weaponization has led to its classification as a select agent most likely to be used as a biological weapon. Unrestricted bacterial growth during the initial preinflammatory phase primes patients to be infectious once disease symptoms begin in the proinflammatory phase, and the rapid disease progression can lead to death before Y. pestis infection can be diagnosed and treated. Using in vivo analyses and focusing on relevant cell types during Pneumonic Plague infection, we can identify host pathways that may be manipulated to extend the treatment window for Pneumonic Plague patients.
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yersinia pestis activates both il 1β and il 1 receptor antagonist to modulate lung inflammation during Pneumonic Plague
PLOS Pathogens, 2015Co-Authors: Roger D Pechous, Vijay Sivaraman, Nikolas M Stasulli, Kara R Eichelberger, Edward A Miao, William E GoldmanAbstract:Pneumonic Plague is the most rapid and lethal form of Yersinia pestis infection. Increasing evidence suggests that Y. pestis employs multiple levels of innate immune evasion and/or suppression to produce an early “pre-inflammatory” phase of pulmonary infection, after which the disease is highly inflammatory in the lung and 100% fatal. In this study, we show that IL-1β/IL-18 cytokine activation occurs early after bacteria enter the lung, and this activation eventually contributes to pulmonary inflammation and pathology during the later stages of infection. However, the inflammatory effects of IL-1β/IL-1-receptor ligation are not observed during this first stage of Pneumonic Plague. We show that Y. pestis also activates the induction of IL-1 receptor antagonist (IL-1RA), and this activation likely contributes to the ability of Y. pestis to establish the initial pre-inflammatory phase of disease.
Stephen T Smiley - One of the best experts on this subject based on the ideXlab platform.
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tnfα and ifnγ contribute to f1 lcrv targeted immune defense in mouse models of fully virulent Pneumonic Plague
Vaccine, 2010Co-Authors: Jr Shiuan Lin, Jim Hill, James B. Bliska, Steven Park, David S. Perlin, Jeffrey J Adamovicz, Christopher K Cote, Kei Amemiya, Stephen T SmileyAbstract:Immunization with the Yersinia pestis F1 and LcrV proteins improves survival in mouse and non-human primate models of Pneumonic Plague. F1- and LcrV-specific antibodies contribute to protection, however, the mechanisms of antibody-mediated defense are incompletely understood and serum antibody titers do not suffice as quantitative correlates of protection. Previously we demonstrated roles for tumor necrosis factor-alpha (TNFα) and gamma-interferon (IFNγ) during defense against conditionally attenuated pigmentation (pgm) locus-negative Y. pestis. Here, using intranasal challenge with fully virulent pgm-positive Y. pestis strain CO92, we demonstrate that neutralizing TNFα and IFNγ interferes with the capacity of therapeutically administered F1- or LcrV-specific antibody to reduce bacterial burden and increase survival. Moreover, using Y. pestis strain CO92 in an aerosol challenge model, we demonstrate that neutralizing TNFα and IFNγ interferes with protection conferred by immunization with recombinant F1-LcrV fusion protein vaccine (p<0.0005). These findings establish that TNFα and IFNγ contribute to protection mediated by Pneumonic Plague countermeasures targeting F1 and LcrV, and suggest that an individual's capacity to produce these cytokines in response to Y. pestis challenge will be an important co-determinant of antibody-mediated defense against Pneumonic Plague.
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d27 plpxl an avirulent strain of yersinia pestis primes t cells that protect against Pneumonic Plague
Infection and Immunity, 2009Co-Authors: Frank M Szaba, Jr Shiuan Lin, Lawrence W Kummer, Michelle A Parent, Lawrence L Johnson, Lindsey B Wilhelm, Sara W Montminypaquette, Egil Lien, Stephen T SmileyAbstract:Vaccinating with live, conditionally attenuated, pigmentation (Pgm)-deficient Yersinia pestis primes T cells that protect mice against Pneumonic Plague. However, Pgm-deficient strains are not considered safe for human use because they retain substantial virulence in animal models. Y. pestis strains engineered to express Escherichia coli LpxL are avirulent owing to constitutive production of lipopolysaccharide with increased Toll-like receptor 4-activating ability. We generated an LpxL-expressing Pgm-deficient strain (D27-pLpxL) and demonstrate here that this avirulent strain retains the capacity to prime protective T cells. Compared with unvaccinated controls, mice immunized intranasally with live D27-pLpxL exhibit a decreased bacterial burden and increased survival when challenged intranasally with virulent Y. pestis. T cells provide a substantial degree of this protection, as vaccine efficacy is maintained in B-cell-deficient μMT mice unless those animals are depleted of CD4 and CD8 T cells at the time of challenge. Upon challenge with Y. pestis, pulmonary T-cell numbers decline in naive mice, whereas immunized mice show increased numbers of CD44high CD43high effector T cells and T cells primed to produce tumor necrosis factor alpha and gamma interferon; neutralizing these cytokines at the time of challenge abrogates protection. Immunization does not prevent dissemination of Y. pestis from the lung but limits bacterial growth and pathology in visceral tissue, apparently by facilitating formation of granuloma-like structures. This study describes a new model for studying T-cell-mediated protection against Pneumonic Plague and demonstrates the capacity for live, highly attenuated, Y. pestis vaccine strains to prime protective memory T-cell responses safely.
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antibodies and cytokines independently protect against Pneumonic Plague
Vaccine, 2008Co-Authors: Lawrence W Kummer, Jeffrey J Adamovicz, Frank M Szaba, Michelle A Parent, James Hill, Lawrence L Johnson, Stephen T SmileyAbstract:Yersinia pestis causes Pneumonic Plague, an exceptionally virulent disease for which we lack a safe and effective vaccine. Antibodies specific for the Y. pestis F1 and LcrV proteins can protect mice against pulmonary Y. pestis infection. We demonstrate that neutralizing tumor necrosis factor-alpha (TNFalpha) and gamma-interferon (IFNgamma) abrogates this protection at sub-optimal levels of F1- or LcrV-specific antibody, but not at optimal levels. Moreover, we demonstrate that endogenous TNFalpha and IFNgamma confer measurable protection in the complete absence of protective antibodies. These findings indicate that antibodies and cytokines independently protect against Pneumonic Plague and suggest that surrogate assays for Plague vaccine efficacy should consider both the level of vaccine-induced antibody and the capacity of vaccine recipients to produce TNFalpha and IFNgamma upon exposure to Y. pestis.
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immune defense against Pneumonic Plague
Immunological Reviews, 2008Co-Authors: Stephen T SmileyAbstract:Yersinia pestis is one of the world's most virulent human pathogens. Inhalation of this Gram-negative bacterium causes Pneumonic Plague, a rapidly progressing and usually fatal disease. Extensively antibiotic-resistant strains of Y. pestis exist and have significant potential for exploitation as agents of terrorism and biowarfare. Subunit vaccines comprised of the Y. pestis F1 and LcrV proteins are well-tolerated and immunogenic in humans but cannot be tested for efficacy, because Pneumonic Plague outbreaks are uncommon and intentional infection of humans is unethical. In animal models, F1/LcrV-based vaccines protect mice and cynomolgus macaques but have failed, thus far, to adequately protect African green monkeys. We lack an explanation for this inconsistent efficacy. We also lack reliable correlate assays for protective immunity. These deficiencies are hampering efforts to improve vaccine efficacy. Here, I review the immunology of Pneumonic Plague, focusing on evidence that humoral and cellular defense mechanisms collaborate to defend against pulmonary Y. pestis infection.
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Current challenges in the development of vaccines for Pneumonic Plague.
Expert review of vaccines, 2008Co-Authors: Stephen T SmileyAbstract:Inhalation of Yersinia pestis bacilli causes Pneumonic Plague, a rapidly progressing and exceptionally virulent disease. Extensively antibiotic-resistant Y. pestis strains exist and we currently lack a safe and effective Pneumonic Plague vaccine. These facts raise concern that Y. pestis may be exploited as a bioweapon. Here, I review the history and status of Plague vaccine research and advocate that Pneumonic Plague vaccines should strive to prime both humoral and cellular immunity.
Roger D Pechous - One of the best experts on this subject based on the ideXlab platform.
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pretreatment with fluticasone propionate increases antibiotic efficacy during treatment of late stage primary Pneumonic Plague
Antimicrobial Agents and Chemotherapy, 2021Co-Authors: Samantha D Crane, Srijon K Banerjee, Roger D PechousAbstract:Severe and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death. In order to effectively treat severe and late-stage pneumonias, use of adjunctive therapies must be considered to reduce pulmonary damage when antimicrobial agents can be administered. Pneumonic Plague, a severe pneumonia caused by inhalation of Yersinia pestis, is a fatal disease that causes death within six days without antibiotic intervention. Late-stage Pneumonic Plague is difficult to treat, as antibiotics must be delivered within 24 hours after onset of symptoms to be effective. Here, we use a murine model of primary Pneumonic Plague to examine how host inflammatory responses impact antibiotic treatment of late-stage Pneumonic Plague. We developed a murine infection model demonstrating the poor outcomes associated with delayed delivery of antibiotics. We show that pretreatment of mice with intranasal fluticasone propionate increased efficacy of delayed antibiotic delivery and enhanced murine survival. Mice receiving fluticasone propionate also showed decreased bacterial burden and reduced inflammatory pathology in the lungs. Further, we show that treatment and survival correlated with decreased levels of IL-6 and reduced neutrophil infiltration to the lungs. This work demonstrates how host inflammatory responses complicate treatment of late-stage Pneumonic Plague, and suggests that targeting of host inflammatory responses may improve treatment of severe, late-stage pneumonia.
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the yersinia pestis gtpase bipa promotes pathogenesis of primary Pneumonic Plague
Infection and Immunity, 2021Co-Authors: Samantha D Crane, William E Goldman, Srijon Kaushik Banerjee, Kara R Eichelberger, Richard C Kurten, Roger D PechousAbstract:ABSTRACT Yersinia pestis is a highly virulent pathogen and the causative agent of bubonic, septicemic, and Pneumonic Plague. Primary Pneumonic Plague caused by inhalation of respiratory droplets contaminated with Y. pestis is nearly 100% lethal within 4 to 7 days without antibiotic intervention. Pneumonic Plague progresses in two phases, beginning with extensive bacterial replication in the lung with minimal host responsiveness, followed by the abrupt onset of a lethal proinflammatory response. The precise mechanisms by which Y. pestis is able to colonize the lung and survive two very distinct disease phases remain largely unknown. To date, a few bacterial virulence factors, including the Ysc type 3 secretion system, are known to contribute to the pathogenesis of primary Pneumonic Plague. The bacterial GTPase BipA has been shown to regulate expression of virulence factors in a number of Gram-negative bacteria, including Pseudomonas aeruginosa, Escherichia coli, and Salmonella enterica serovar Typhi. However, the role of BipA in Y. pestis has yet to be investigated. Here, we show that BipA is a Y. pestis virulence factor that promotes defense against early neutrophil-mediated bacterial killing in the lung. This work identifies a novel Y. pestis virulence factor and highlights the importance of early bacterial/neutrophil interactions in the lung during primary Pneumonic Plague.
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a dual role for the plasminogen activator protease during the preinflammatory phase of primary Pneumonic Plague
The Journal of Infectious Diseases, 2020Co-Authors: Srijon Kaushik Banerjee, Samantha D Crane, Roger D PechousAbstract:Early after inhalation, Yersinia pestis replicates to high numbers in the airways in the absence of disease symptoms or notable inflammatory responses to cause primary Pneumonic Plague. The plasminogen activator protease (Pla) is a critical Y. pestis virulence factor that is important for early bacterial growth in the lung via an unknown mechanism. In this article, we define a dual role for Pla in the initial stages of pulmonary infection. We show that Pla functions as an adhesin independent of its proteolytic function to suppress early neutrophil influx into the lungs, and that Pla enzymatic activity contributes to bacterial resistance to neutrophil-mediated bacterial killing. Our results suggest that the fate of Y. pestis infection of the lung is decided extremely early during infection and that Pla plays a dual role to tilt the balance in favor of the pathogen.
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modeling Pneumonic Plague in human precision cut lung slices highlights a role for the plasminogen activator protease in facilitating type 3 secretion
Infection and Immunity, 2019Co-Authors: Srijon Kaushik Banerjee, Richard C Kurten, Samantha D Huckuntod, Shalynn D Mills, Roger D PechousAbstract:Pneumonic Plague is the deadliest form of disease caused by Yersinia pestis Key to the progression of infection is the activity of the plasminogen activator protease Pla. Deletion of Pla results in a decreased Y. pestis bacterial burden in the lung and failure to progress into the lethal proinflammatory phase of disease. While a number of putative functions have been attributed to Pla, its precise role in the pathogenesis of Pneumonic Plague is yet to be defined. Here, we show that Pla facilitates type 3 secretion into primary alveolar macrophages but not into the commonly used THP-1 cell line. We also establish human precision-cut lung slices as a platform for modeling early host/pathogen interactions during Pneumonic Plague and solidify the role of Pla in promoting optimal type 3 secretion using primary human tissue with relevant host cell heterogeneity. These results position Pla as a key player in the early host/pathogen interactions that define Pneumonic Plague and showcase the utility of human precision-cut lung slices as a platform to evaluate pulmonary infection by bacterial pathogens.
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Pneumonic Plague the darker side of yersinia pestis
Trends in Microbiology, 2016Co-Authors: Roger D Pechous, Vijay Sivaraman, Nikolas M Stasulli, William E GoldmanAbstract:Inhalation of the bacterium Yersinia pestis results in primary Pneumonic Plague. Pneumonic Plague is the most severe manifestation of Plague, with mortality rates approaching 100% in the absence of treatment. Its rapid disease progression, lethality, and ability to be transmitted via aerosol have compounded fears of the intentional release of Y. pestis as a biological weapon. Importantly, recent epidemics of Plague have highlighted a significant role for Pneumonic Plague during outbreaks of Y. pestis infections. In this review we describe the characteristics of Pneumonic Plague, focusing on its disease progression and pathogenesis. The rapid time-course, severity, and difficulty of treating Pneumonic Plague highlight how differences in the route of disease transmission can enhance the lethality of an already deadly pathogen.
Emanuelle Mamroud - One of the best experts on this subject based on the ideXlab platform.
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postexposure administration of a yersinia pestis live vaccine for potentiation of second line antibiotic treatment against Pneumonic Plague
The Journal of Infectious Diseases, 2019Co-Authors: Ayelet Zauberman, David Gur, Yinon Levy, Moshe Aftalion, Yaron Vagima, Avital Tidhar, Theodor Chitlaru, Emanuelle MamroudAbstract:Pneumonic Plague, caused by Yersinia pestis, is a rapidly progressing contagious disease. In the Plague mouse model, a single immunization with the EV76 live attenuated Y. pestis strain rapidly induced the expression of hemopexin and haptoglobin in the lung and serum, both of which are important in iron sequestration. Immunization against a concomitant lethal Y. pestis respiratory challenge was correlated with temporary inhibition of disease progression. Combining EV76-immunization and second-line antibiotic treatment, which are individually insufficient, led to a synergistic protective effect that represents a proof of concept for efficient combinational therapy in cases of infection with antibiotic-resistant strains.
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circumventing y pestis virulence by early recruitment of neutrophils to the lungs during Pneumonic Plague
PLOS Pathogens, 2015Co-Authors: Yaron Vagima, Ayelet Zauberman, David Gur, Yinon Levy, Moshe Aftalion, Avital Tidhar, Avigdor Shafferman, Emanuelle MamroudAbstract:Pneumonic Plague is a fatal disease caused by Yersinia pestis that is associated with a delayed immune response in the lungs. Because neutrophils are the first immune cells recruited to sites of infection, we investigated the mechanisms responsible for their delayed homing to the lung. During the first 24 hr after pulmonary infection with a fully virulent Y. pestis strain, no significant changes were observed in the lungs in the levels of neutrophils infiltrate, expression of adhesion molecules, or the expression of the major neutrophil chemoattractants keratinocyte cell-derived chemokine (KC), macrophage inflammatory protein 2 (MIP-2) and granulocyte colony stimulating factor (G-CSF). In contrast, early induction of chemokines, rapid neutrophil infiltration and a reduced bacterial burden were observed in the lungs of mice infected with an avirulent Y. pestis strain. In vitro infection of lung-derived cell-lines with a YopJ mutant revealed the involvement of YopJ in the inhibition of chemoattractants expression. However, the recruitment of neutrophils to the lungs of mice infected with the mutant was still delayed and associated with rapid bacterial propagation and mortality. Interestingly, whereas KC, MIP-2 and G-CSF mRNA levels in the lungs were up-regulated early after infection with the mutant, their protein levels remained constant, suggesting that Y. pestis may employ additional mechanisms to suppress early chemoattractants induction in the lung. It therefore seems that prevention of the early influx of neutrophils to the lungs is of major importance for Y. pestis virulence. Indeed, pulmonary instillation of KC and MIP-2 to G-CSF-treated mice infected with Y. pestis led to rapid homing of neutrophils to the lung followed by a reduction in bacterial counts at 24 hr post-infection and improved survival rates. These observations shed new light on the virulence mechanisms of Y. pestis during Pneumonic Plague, and have implications for the development of novel therapies against this pathogen.
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yersinia pestis endowed with increased cytotoxicity is avirulent in a bubonic Plague model and induces rapid protection against Pneumonic Plague
PLOS ONE, 2009Co-Authors: Ayelet Zauberman, Yinon Levy, Avital Tidhar, Avigdor Shafferman, Erez Barhaim, Gideon Halperin, Yehuda Flashner, Sara Cohen, Emanuelle MamroudAbstract:An important virulence strategy evolved by bacterial pathogens to overcome host defenses is the modulation of host cell death. Previous observations have indicated that Yersinia pestis, the causative agent of Plague disease, exhibits restricted capacity to induce cell death in macrophages due to ineffective translocation of the type III secretion effector YopJ, as opposed to the readily translocated YopP, the YopJ homologue of the enteropathogen Yersinia enterocolitica O∶8. This led us to suggest that reduced cytotoxic potency may allow pathogen propagation within a shielded niche, leading to increased virulence. To test the relationship between cytotoxic potential and virulence, we replaced Y. pestis YopJ with YopP. The YopP-expressing Y. pestis strain exhibited high cytotoxic activity against macrophages in vitro. Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 107-fold reduction in virulence. Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain. The subcutaneous administration of the cytotoxic Y. pestis strain appears to activate a rapid and potent systemic, CTL-independent, immunoprotective response, allowing the organism to overcome simultaneous coinfection with 10,000 LD50 of virulent Y. pestis. Moreover, three days after subcutaneous administration of this strain, animals were also protected against septicemic or primary Pneumonic Plague. Our findings indicate that an inverse relationship exists between the cytotoxic potential of Y. pestis and its virulence following subcutaneous infection. This appears to be associated with the ability of the engineered cytotoxic Y. pestis strain to induce very rapid, effective and long-lasting protection against bubonic and Pneumonic Plague. These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the virulence strategies of Y. pestis in nature.