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  • 1
    Publication Date: 2013-02-21
    Description: Bacillus cereus strains harboring a pXO1-like virulence plasmid cause respiratory anthrax-like disease in humans, particularly in welders. We developed mouse models for intraperitoneal as well as aerosol challenge with spores of B. cereus G9241, harboring pBCXO1 and pBC218 virulence plasmids. Compared to wild-type B. cereus G9241, spores with a deletion of the pBCXO1-carried protective antigen gene ( pagA1 ) were severely attenuated, whereas spores with a deletion of the pBC218-carried protective antigen homologue ( pagA2 ) were not. Anthrax vaccine adsorbed (AVA) immunization raised antibodies that bound and neutralized the pagA1 -encoded protective antigen (PA1) but not the PA2 orthologue encoded by pagA2 . AVA immunization protected mice against a lethal challenge with spores from B. cereus G9241 or B. cereus Elc4, a strain that had been isolated from a fatal case of anthrax-like disease. As the pathogenesis of B. cereus anthrax-like disease in mice is dependent on pagA1 and PA-neutralizing antibodies provide protection, AVA immunization may also protect humans from respiratory anthrax-like death.
    Print ISSN: 0019-9567
    Electronic ISSN: 1098-5522
    Topics: Medicine
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  • 2
    Publication Date: 2015-11-11
    Description: Many pathogens usurp the host hemostatic system during infection to promote pathogenesis. Yersinia pestis , the causative agent of plague, expresses the plasminogen activator protease Pla, which has been shown in vitro to target and cleave multiple proteins within the fibrinolytic pathway, including the plasmin inhibitor α2-antiplasmin (A2AP). It is not known, however, if Pla inactivates A2AP in vivo ; the role of A2AP during respiratory Y. pestis infection is not known either. Here, we show that Y. pestis does not appreciably cleave A2AP in a Pla-dependent manner in the lungs during experimental pneumonic plague. Furthermore, following intranasal infection with Y. pestis , A2AP-deficient mice exhibit no difference in survival time, bacterial burden in the lungs, or dissemination from wild-type mice. Instead, we found that in the absence of Pla, A2AP contributes to the control of the pulmonary inflammatory response during infection by reducing neutrophil recruitment and cytokine production, resulting in altered immunopathology of the lungs compared to A2AP-deficient mice. Thus, our data demonstrate that A2AP is not significantly affected by the Pla protease during pneumonic plague, and although A2AP participates in immune modulation in the lungs, it has limited impact on the course or ultimate outcome of the infection.
    Print ISSN: 0019-9567
    Electronic ISSN: 1098-5522
    Topics: Medicine
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  • 3
    Publication Date: 2015-12-29
    Description: Pneumonic plague represents the most severe form of disease caused by Yersinia pestis due to its ease of transmission, rapid progression, and high mortality rate. The Y. pestis outer membrane Pla protease is essential for the development of pneumonic plague; however, the complete repertoire of substrates cleaved by Pla in the lungs is not known. In this study, we describe a proteomic screen to identify host proteins contained within the bronchoalveolar lavage fluid of mice that are cleaved and/or processed by Y. pestis in a Pla-dependent manner. We identified peroxiredoxin 6 (Prdx6), a host factor that contributes to pulmonary surfactant metabolism and lung defense against oxidative stress, as a previously unknown substrate of Pla. Pla cleaves Prdx6 at three distinct sites, and these cleavages disrupt both the peroxidase and phospholipase A 2 activities of Prdx6. In addition, we found that infection with wild-type Y. pestis reduces the abundance of extracellular Prdx6 in the lungs compared to that after infection with pla Y. pestis , suggesting that Pla cleaves Prdx6 in the pulmonary compartment. However, following infection with either wild-type or pla Y. pestis , Prdx6-deficient mice exhibit no differences in bacterial burden, host immune response, or lung damage from wild-type mice. Thus, while Pla is able to disrupt Prdx6 function in vitro and reduce Prdx6 levels in vivo , the cleavage of Prdx6 has little detectable impact on the progression or outcome of pneumonic plague.
    Print ISSN: 0019-9567
    Electronic ISSN: 1098-5522
    Topics: Medicine
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  • 4
    Publication Date: 2015-07-23
    Description: Objectives To investigate researchers’ perceptions about the factors that influenced the policy and practice impacts (or lack of impact) of one of their own funded intervention research studies. Design Mixed method, cross-sectional study. Setting Intervention research conducted in Australia and funded by Australia's National Health and Medical Research Council between 2003 and 2007. Participants The chief investigators from 50 funded intervention research studies were interviewed to determine if their study had achieved policy and practice impacts, how and why these impacts had (or had not) occurred and the approach to dissemination they had employed. Results We found that statistically significant intervention effects and publication of results influenced whether there were policy and practice impacts, along with factors related to the nature of the intervention itself, the researchers’ experience and connections, their dissemination and translation efforts, and the postresearch context. Conclusions This study indicates that sophisticated approaches to intervention development, dissemination actions and translational efforts are actually widespread among experienced researches, and can achieve policy and practice impacts. However, it was the links between the intervention results, further dissemination actions by researchers and a variety of postresearch contextual factors that ultimately determined whether a study had policy and practice impacts. Given the complicated interplay between the various factors, there appears to be no simple formula for determining which intervention studies should be funded in order to achieve optimal policy and practice impacts.
    Keywords: Open access, Evidence based practice, Health policy, Research methods
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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