The Experts below are selected from a list of 19782 Experts worldwide ranked by ideXlab platform
Annemarie H. Meijer - One of the best experts on this subject based on the ideXlab platform.
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The selective autophagy receptors Optineurin and p62 are both required for zebrafish host resistance to Mycobacterial Infection.
PLOS Pathogens, 2019Co-Authors: Rui Zhang, Monica Varela, Wies Vallentgoed, Michiel Van Der Vaart, Gabriel Forn-cuní, Annemarie H. MeijerAbstract:Mycobacterial pathogens are the causative agents of chronic infectious diseases like tuberculosis and leprosy. Autophagy has recently emerged as an innate mechanism for defense against these intracellular pathogens. In vitro studies have shown that mycobacteria escaping from phagosomes into the cytosol are ubiquitinated and targeted by selective autophagy receptors. However, there is currently no in vivo evidence for the role of selective autophagy receptors in defense against mycobacteria, and the importance of autophagy in control of Mycobacterial diseases remains controversial. Here we have used Mycobacterium marinum (Mm), which causes a tuberculosis-like disease in zebrafish, to investigate the function of two selective autophagy receptors, Optineurin (Optn) and SQSTM1 (p62), in host defense against a Mycobacterial pathogen. To visualize the autophagy response to Mm in vivo, optn and p62 zebrafish mutant lines were generated in the background of a GFP-Lc3 autophagy reporter line. We found that loss-of-function mutation of optn or p62 reduces autophagic targeting of Mm, and increases susceptibility of the zebrafish host to Mm Infection. Transient knockdown studies confirmed the requirement of both selective autophagy receptors for host resistance against Mm Infection. For gain-of-function analysis, we overexpressed optn or p62 by mRNA injection and found this to increase the levels of GFP-Lc3 puncta in association with Mm and to reduce the Mm Infection burden. Taken together, our results demonstrate that both Optn and p62 are required for autophagic host defense against Mycobacterial Infection and support that protection against tuberculosis disease may be achieved by therapeutic strategies that enhance selective autophagy.
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hif 1α induced expression of il 1β protects against Mycobacterial Infection in zebrafish
Journal of Immunology, 2019Co-Authors: Annemarie H. Meijer, Stephen A Renshaw, Nikolay V Ogryzko, Amy Lewis, Heather L Wilson, Philip M ElksAbstract:Drug-resistant mycobacteria are a rising problem worldwide. There is an urgent need to understand the immune response to tuberculosis to identify host targets that, if targeted therapeutically, could be used to tackle these currently untreatable Infections. In this study we use an Il-1β fluorescent transgenic line to show that there is an early innate immune proinflammatory response to well-established zebrafish models of inflammation and Mycobacterium marinum Infection. We demonstrate that host-derived hypoxia signaling, mediated by the Hif-1α transcription factor, can prime macrophages with increased levels of Il-1β in the absence of Infection, upregulating neutrophil antimicrobial NO production, leading to greater protection against Infection. Our data link Hif-1α to proinflammatory macrophage Il-1β transcription in vivo during early Mycobacterial Infection and importantly highlight a host protective mechanism, via antimicrobial NO, that decreases disease outcomes and that could be targeted therapeutically to stimulate the innate immune response to better deal with Infections.
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The selective autophagy receptors Optineurin and p62 are both required for innate host defense against Mycobacterial Infection
bioRxiv, 2018Co-Authors: Rui Zhang, Monica Varela, Wies Vallentgoed, Michiel Van Der Vaart, Annemarie H. MeijerAbstract:Mycobacterial pathogens are the causative agents of chronic infectious diseases like tuberculosis and leprosy. Autophagy has recently emerged as an innate mechanism for defense against these intracellular pathogens. In vitro studies have shown that mycobacteria escaping from phagosomes into the cytosol are ubiquitinated and targeted by selective autophagy receptors. However, there is currently no in vivo evidence for the role of selective autophagy receptors in defense against mycobacteria, and the importance of autophagy in control of Mycobacterial diseases remains controversial. Here we have used Mycobacterium marinum (Mm), which causes a tuberculosis-like disease in zebrafish, to investigate the function of two selective autophagy receptors, Optineurin (Optn) and SQSTM1 (p62), in host defense against a Mycobacterial pathogen. To visualize the autophagy response to Mm in vivo, optn and p62 zebrafish mutant lines were generated in the background of a GFP-Lc3 autophagy reporter line. We found that loss-of-function mutation of optn or p62 reduces autophagic targeting of Mm, and increases susceptibility of the zebrafish host to Mm Infection. Transient knockdown studies confirmed the requirement of both selective autophagy receptors for host resistance against Mm Infection. For gain-of-function analysis, we overexpressed optn or p62 by mRNA injection and found this to increase the levels of GFP-Lc3 puncta in association with Mm and to reduce the Mm Infection burden. Taken together, our results demonstrate that both Optineurin and p62 are required for autophagic host defense against Mycobacterial Infection and support that protection against tuberculosis disease may be achieved by therapeutic strategies that enhance selective autophagy.
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macrophage il 1beta protects against Mycobacterial Infection downstream of hif 1alpha in zebrafish
bioRxiv, 2018Co-Authors: Nikolay V Ogryzko, Annemarie H. Meijer, Stephen A Renshaw, Amy Lewis, Heather L Wilson, Philip M ElksAbstract:Drug resistant mycobacteria are a rising problem worldwide. There is an urgent need to understand the immune response to TB to identify host targets that, if targeted therapeutically, could be used to tackle these currently untreatable Infections. Here, we use an Il-1β; fluorescent transgenic line to show that there is an early innate immune pro-inflammatory response to well-established zebrafish models of inflammation and Mycobacterium marinum (Mm) Infection. We demonstrate that host-derived hypoxia signalling, mediated by the Hif-1α; transcription factor, can prime macrophages with increased levels of Il-1β; in the absence of Infection, upregulating neutrophil antimicrobial nitric oxide production, leading to greater protection against Infection. Our data link Hif-1α; to proinflammatory macrophage Il-1β; transcription in vivo during early Mycobacterial Infection and importantly highlight a host protective mechanism, via antimicrobial nitric oxide, that decreases disease outcomes and that could be targeted therapeutically to stimulate the innate immune response to better deal with Infections.
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the cxcr3 cxcl11 signaling axis mediates macrophage recruitment and dissemination of Mycobacterial Infection
Disease Models & Mechanisms, 2015Co-Authors: Vincenzo Torraca, Astrid M Van Der Sar, Herman P Spaink, Chao Cui, Ralf Boland, J P Bebelman, Martine J Smit, Marco Siderius, Annemarie H. MeijerAbstract:The recruitment of leukocytes to infectious foci depends strongly on the local release of chemoattractant mediators. The human CXC chemokine receptor 3 (CXCR3) is an important node in the chemokine signaling network and is expressed by multiple leukocyte lineages, including T cells and macrophages. The ligands of this receptor originate from an ancestral CXCL11 gene in early vertebrates. Here, we used the optically accessible zebrafish embryo model to explore the function of the CXCR3-CXCL11 axis in macrophage recruitment and show that disruption of this axis increases the resistance to Mycobacterial Infection. In a mutant of the zebrafish ortholog of CXCR3 (cxcr3.2), macrophage chemotaxis to bacterial Infections was attenuated, although migration to Infection-independent stimuli was unaffected. Additionally, attenuation of macrophage recruitment to Infection could be mimicked by treatment with NBI74330, a high-affinity antagonist of CXCR3. We identified two Infection-inducible CXCL11-like chemokines as the functional ligands of Cxcr3.2, showing that the recombinant proteins exerted a Cxcr3.2-dependent chemoattraction when locally administrated in vivo. During Infection of zebrafish embryos with Mycobacterium marinum, a well-established model for tuberculosis, we found that Cxcr3.2 deficiency limited the macrophage-mediated dissemination of mycobacteria. Furthermore, the loss of Cxcr3.2 function attenuated the formation of granulomatous lesions, the typical histopathological features of tuberculosis, and led to a reduction in the total bacterial burden. Prevention of Mycobacterial dissemination by targeting the CXCR3 pathway, therefore, might represent a host-directed therapeutic strategy for treatment of tuberculosis. The demonstration of a conserved CXCR3-CXCL11 signaling axis in zebrafish extends the translational applicability of this model for studying diseases involving the innate immune system.
Stefan H Oehlers - One of the best experts on this subject based on the ideXlab platform.
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Thrombocyte Inhibition Restores Protective Immunity to Mycobacterial Infection in Zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, Johansen, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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thrombocyte inhibition restores protective immunity to Mycobacterial Infection in zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:BACKGROUND Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. METHODS In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. RESULTS We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. CONCLUSIONS Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
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thrombocyte inhibition restores protective immunity to Mycobacterial Infection in zebrafish
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:Abstract Infection-induced thrombocytosis is a clinically important complication of tuberculosis (TB). Recent studies have separately highlighted a correlation of platelet activation with TB severity and utility of aspirin as a host-directed therapy for TB that modulates the inflammatory response. Here we investigate the possibility that the beneficial effects of aspirin are related to an anti-platelet mode of action. We utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin or platelet-specific glycoprotein IIb/IIIa inhibitors reduced Mycobacterial burden demonstrating a detrimental role for Infection-induced thrombocyte activation. We found platelet inhibition reduced thrombocyte-macrophage interactions and restored indices of macrophage-mediated immunity to Mycobacterial Infection. Pathological thrombocyte activation and granuloma formation were found to be intrinsically linked illustrating a bidirectional relationship between host hemostasis and TB pathogenesis. Our study illuminates platelet activation as an efficacious target of anti-platelets drugs including aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. Key Points Inhibition of thrombocyte activation improves control of Mycobacterial Infection. Inhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against Mycobacterial Infection.
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analysis of Mycobacterial Infection induced changes to host lipid metabolism in a zebrafish Infection model reveals a conserved role for ldlr in Infection susceptibility
Fish & Shellfish Immunology, 2018Co-Authors: Matt D Johansen, Elinor Hortle, Warwick J Britton, Joshua A Kasparian, Alejandro Romero, Beatriz Novoa, Antonio Figueras, Kumidika De Silva, Auriol C Purdie, Stefan H OehlersAbstract:Abstract Changes to lipid metabolism are well-characterised consequences of human tuberculosis Infection but their functional relevance are not clearly elucidated in these or other host-Mycobacterial systems. The zebrafish-Mycobacterium marinum Infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of Infection-induced lipid metabolism. We find mammalian Mycobacterial Infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of Mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected Infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for Infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-Mycobacterial species pairings.
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Thrombocyte inhibition restores protective immunity to Mycobacterial Infection
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection, but have not investigated the possibility that the effect of aspirin is related to an anti-platelet mode of action. Here we utilise the zebrafish-Mycobacterium marinum model to show mycobacteria drive host haemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
Warwick J Britton - One of the best experts on this subject based on the ideXlab platform.
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Thrombocyte Inhibition Restores Protective Immunity to Mycobacterial Infection in Zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, Johansen, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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thrombocyte inhibition restores protective immunity to Mycobacterial Infection in zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:BACKGROUND Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. METHODS In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. RESULTS We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. CONCLUSIONS Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
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thrombocyte inhibition restores protective immunity to Mycobacterial Infection in zebrafish
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:Abstract Infection-induced thrombocytosis is a clinically important complication of tuberculosis (TB). Recent studies have separately highlighted a correlation of platelet activation with TB severity and utility of aspirin as a host-directed therapy for TB that modulates the inflammatory response. Here we investigate the possibility that the beneficial effects of aspirin are related to an anti-platelet mode of action. We utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin or platelet-specific glycoprotein IIb/IIIa inhibitors reduced Mycobacterial burden demonstrating a detrimental role for Infection-induced thrombocyte activation. We found platelet inhibition reduced thrombocyte-macrophage interactions and restored indices of macrophage-mediated immunity to Mycobacterial Infection. Pathological thrombocyte activation and granuloma formation were found to be intrinsically linked illustrating a bidirectional relationship between host hemostasis and TB pathogenesis. Our study illuminates platelet activation as an efficacious target of anti-platelets drugs including aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. Key Points Inhibition of thrombocyte activation improves control of Mycobacterial Infection. Inhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against Mycobacterial Infection.
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analysis of Mycobacterial Infection induced changes to host lipid metabolism in a zebrafish Infection model reveals a conserved role for ldlr in Infection susceptibility
Fish & Shellfish Immunology, 2018Co-Authors: Matt D Johansen, Elinor Hortle, Warwick J Britton, Joshua A Kasparian, Alejandro Romero, Beatriz Novoa, Antonio Figueras, Kumidika De Silva, Auriol C Purdie, Stefan H OehlersAbstract:Abstract Changes to lipid metabolism are well-characterised consequences of human tuberculosis Infection but their functional relevance are not clearly elucidated in these or other host-Mycobacterial systems. The zebrafish-Mycobacterium marinum Infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of Infection-induced lipid metabolism. We find mammalian Mycobacterial Infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of Mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected Infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for Infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-Mycobacterial species pairings.
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Thrombocyte inhibition restores protective immunity to Mycobacterial Infection
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection, but have not investigated the possibility that the effect of aspirin is related to an anti-platelet mode of action. Here we utilise the zebrafish-Mycobacterium marinum model to show mycobacteria drive host haemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
David M Tobin - One of the best experts on this subject based on the ideXlab platform.
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Thrombocyte Inhibition Restores Protective Immunity to Mycobacterial Infection in Zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, Johansen, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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thrombocyte inhibition restores protective immunity to Mycobacterial Infection in zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:BACKGROUND Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. METHODS In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. RESULTS We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. CONCLUSIONS Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
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potentiation of p2rx7 as a host directed strategy for control of Mycobacterial Infection
eLife, 2019Co-Authors: Molly A Matty, Daphne R Knudsen, Eric M Walton, Rebecca W Beerman, Mark R Cronan, Charlie J Pyle, Rafael E Hernandez, David M TobinAbstract:Mycobacterium tuberculosis is the leading worldwide cause of death due to a single infectious agent. Existing anti-tuberculous therapies require long treatments and are complicated by multi-drug-resistant strains. Host-directed therapies have been proposed as an orthogonal approach, but few have moved into clinical trials. Here, we use the zebrafish-Mycobacterium marinum Infection model as a whole-animal screening platform to identify FDA-approved, host-directed compounds. We identify multiple compounds that modulate host immunity to limit Mycobacterial disease, including the inexpensive, safe, and widely used drug clemastine. We find that clemastine alters macrophage calcium transients through potentiation of the purinergic receptor P2RX7. Host-directed drug activity in zebrafish larvae depends on both P2RX7 and inflammasome signaling. Thus, targeted activation of a P2RX7 axis provides a novel strategy for enhanced control of Mycobacterial Infections. Using a novel explant model, we find that clemastine is also effective within the complex granulomas that are the hallmark of Mycobacterial Infection.
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thrombocyte inhibition restores protective immunity to Mycobacterial Infection in zebrafish
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:Abstract Infection-induced thrombocytosis is a clinically important complication of tuberculosis (TB). Recent studies have separately highlighted a correlation of platelet activation with TB severity and utility of aspirin as a host-directed therapy for TB that modulates the inflammatory response. Here we investigate the possibility that the beneficial effects of aspirin are related to an anti-platelet mode of action. We utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin or platelet-specific glycoprotein IIb/IIIa inhibitors reduced Mycobacterial burden demonstrating a detrimental role for Infection-induced thrombocyte activation. We found platelet inhibition reduced thrombocyte-macrophage interactions and restored indices of macrophage-mediated immunity to Mycobacterial Infection. Pathological thrombocyte activation and granuloma formation were found to be intrinsically linked illustrating a bidirectional relationship between host hemostasis and TB pathogenesis. Our study illuminates platelet activation as an efficacious target of anti-platelets drugs including aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. Key Points Inhibition of thrombocyte activation improves control of Mycobacterial Infection. Inhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against Mycobacterial Infection.
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Thrombocyte inhibition restores protective immunity to Mycobacterial Infection
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection, but have not investigated the possibility that the effect of aspirin is related to an anti-platelet mode of action. Here we utilise the zebrafish-Mycobacterium marinum model to show mycobacteria drive host haemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
Elinor Hortle - One of the best experts on this subject based on the ideXlab platform.
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Thrombocyte Inhibition Restores Protective Immunity to Mycobacterial Infection in Zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, Johansen, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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thrombocyte inhibition restores protective immunity to Mycobacterial Infection in zebrafish
The Journal of Infectious Diseases, 2019Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:BACKGROUND Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection but have not investigated the possibility that the effect of aspirin is related to an antiplatelet mode of action. METHODS In this study, we utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. RESULTS We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation, providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. CONCLUSIONS Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
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thrombocyte inhibition restores protective immunity to Mycobacterial Infection in zebrafish
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:Abstract Infection-induced thrombocytosis is a clinically important complication of tuberculosis (TB). Recent studies have separately highlighted a correlation of platelet activation with TB severity and utility of aspirin as a host-directed therapy for TB that modulates the inflammatory response. Here we investigate the possibility that the beneficial effects of aspirin are related to an anti-platelet mode of action. We utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin or platelet-specific glycoprotein IIb/IIIa inhibitors reduced Mycobacterial burden demonstrating a detrimental role for Infection-induced thrombocyte activation. We found platelet inhibition reduced thrombocyte-macrophage interactions and restored indices of macrophage-mediated immunity to Mycobacterial Infection. Pathological thrombocyte activation and granuloma formation were found to be intrinsically linked illustrating a bidirectional relationship between host hemostasis and TB pathogenesis. Our study illuminates platelet activation as an efficacious target of anti-platelets drugs including aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis. Key Points Inhibition of thrombocyte activation improves control of Mycobacterial Infection. Inhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against Mycobacterial Infection.
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analysis of Mycobacterial Infection induced changes to host lipid metabolism in a zebrafish Infection model reveals a conserved role for ldlr in Infection susceptibility
Fish & Shellfish Immunology, 2018Co-Authors: Matt D Johansen, Elinor Hortle, Warwick J Britton, Joshua A Kasparian, Alejandro Romero, Beatriz Novoa, Antonio Figueras, Kumidika De Silva, Auriol C Purdie, Stefan H OehlersAbstract:Abstract Changes to lipid metabolism are well-characterised consequences of human tuberculosis Infection but their functional relevance are not clearly elucidated in these or other host-Mycobacterial systems. The zebrafish-Mycobacterium marinum Infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of Infection-induced lipid metabolism. We find mammalian Mycobacterial Infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of Mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected Infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for Infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-Mycobacterial species pairings.
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Thrombocyte inhibition restores protective immunity to Mycobacterial Infection
bioRxiv, 2018Co-Authors: Elinor Hortle, Khelsey E Johnson, David M Tobin, Warwick J Britton, Tuong Van Nguyen, Jordan A. Shavit, Matt D Johansen, Stefan H OehlersAbstract:Infection-induced thrombocytosis is a clinically important complication of tuberculosis Infection. Recent studies have highlighted the utility of aspirin as a host-directed therapy modulating the inflammatory response to Infection, but have not investigated the possibility that the effect of aspirin is related to an anti-platelet mode of action. Here we utilise the zebrafish-Mycobacterium marinum model to show mycobacteria drive host haemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin markedly reduced Mycobacterial burden. This effect is reproduced by treatment with platelet-specific glycoprotein IIb/IIIa inhibitors demonstrating a detrimental role for Infection-induced thrombocyte activation. We find that the reduction in Mycobacterial burden is dependent on macrophages and granuloma formation providing the first in vivo experimental evidence that Infection-induced platelet activation compromises protective host immunity to Mycobacterial Infection. Our study illuminates platelet activation as an efficacious target of aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.
