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Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis

BACKGROUND: Melioidosis, caused by the gram-negative bacterium Burkholderia pseudomallei, is a common cause of community-acquired sepsis in Southeast Asia and Northern Australia. The NLRP3 inflammasome and its downstream product interleukin-1 beta (IL-1β) have been proposed to play crucial roles in...

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Autores principales: Weehuizen, Tassili A. F., Lankelma, Jacqueline M., De Jong, Hanna K., De Boer, Onno J., Roelofs, Joris J. T. H., Day, Nicholas P., Gram, Hermann, De Vos, Alex F., Wiersinga, W. Joost
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058638/
https://www.ncbi.nlm.nih.gov/pubmed/27219859
http://dx.doi.org/10.1097/SHK.0000000000000625
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author Weehuizen, Tassili A. F.
Lankelma, Jacqueline M.
De Jong, Hanna K.
De Boer, Onno J.
Roelofs, Joris J. T. H.
Day, Nicholas P.
Gram, Hermann
De Vos, Alex F.
Wiersinga, W. Joost
author_facet Weehuizen, Tassili A. F.
Lankelma, Jacqueline M.
De Jong, Hanna K.
De Boer, Onno J.
Roelofs, Joris J. T. H.
Day, Nicholas P.
Gram, Hermann
De Vos, Alex F.
Wiersinga, W. Joost
author_sort Weehuizen, Tassili A. F.
collection PubMed
description BACKGROUND: Melioidosis, caused by the gram-negative bacterium Burkholderia pseudomallei, is a common cause of community-acquired sepsis in Southeast Asia and Northern Australia. The NLRP3 inflammasome and its downstream product interleukin-1 beta (IL-1β) have been proposed to play crucial roles in melioidosis. In this study, we characterized the role of IL-1β more closely and we assessed its therapeutic potential. METHODS: mRNA expression of inflammasome components was determined in isolated leukocytes of 32 healthy controls and 34 patients with sepsis caused by B pseudomallei. Wild-type (WT), NLRP3-deficient (Nlrp3(−/−)), and Asc(−/−) mice were infected with B pseudomallei. In additional experiments, infected WT mice were treated with an anti-IL-1β antibody. After 24, 48, and 72 hours (h) mice were sacrificed and organs were harvested. Furthermore, survival studies were performed. RESULTS: Patients with melioidosis exhibited lower mRNA levels of caspase-1, NLRP3, and ASC. Bacterial dissemination and organ damage were increased in B pseudomallei-infected Nlrp3(−/−) and Asc(−/−) mice, together with a reduced pulmonary cell influx. Anti-IL-1β treatment of B pseudomallei challenged mice resulted in strongly reduced bacterial counts, organ damage, and pulmonary granulocyte influx together with reduced mortality. Postponement of anti-IL-1β treatment for 24 h postinfection still protected mice during melioidosis. CONCLUSION: Expression of caspase-1, NLRP3, and ASC is altered in melioidosis patients. In mice, both NLRP3 and ASC contribute to the host defense against melioidosis. Anti-IL-1β treatment protects mice against B pseudomallei infection and might be a novel treatment strategy in melioidosis.
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spelling pubmed-50586382016-10-28 Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis Weehuizen, Tassili A. F. Lankelma, Jacqueline M. De Jong, Hanna K. De Boer, Onno J. Roelofs, Joris J. T. H. Day, Nicholas P. Gram, Hermann De Vos, Alex F. Wiersinga, W. Joost Shock Basic Science Aspects BACKGROUND: Melioidosis, caused by the gram-negative bacterium Burkholderia pseudomallei, is a common cause of community-acquired sepsis in Southeast Asia and Northern Australia. The NLRP3 inflammasome and its downstream product interleukin-1 beta (IL-1β) have been proposed to play crucial roles in melioidosis. In this study, we characterized the role of IL-1β more closely and we assessed its therapeutic potential. METHODS: mRNA expression of inflammasome components was determined in isolated leukocytes of 32 healthy controls and 34 patients with sepsis caused by B pseudomallei. Wild-type (WT), NLRP3-deficient (Nlrp3(−/−)), and Asc(−/−) mice were infected with B pseudomallei. In additional experiments, infected WT mice were treated with an anti-IL-1β antibody. After 24, 48, and 72 hours (h) mice were sacrificed and organs were harvested. Furthermore, survival studies were performed. RESULTS: Patients with melioidosis exhibited lower mRNA levels of caspase-1, NLRP3, and ASC. Bacterial dissemination and organ damage were increased in B pseudomallei-infected Nlrp3(−/−) and Asc(−/−) mice, together with a reduced pulmonary cell influx. Anti-IL-1β treatment of B pseudomallei challenged mice resulted in strongly reduced bacterial counts, organ damage, and pulmonary granulocyte influx together with reduced mortality. Postponement of anti-IL-1β treatment for 24 h postinfection still protected mice during melioidosis. CONCLUSION: Expression of caspase-1, NLRP3, and ASC is altered in melioidosis patients. In mice, both NLRP3 and ASC contribute to the host defense against melioidosis. Anti-IL-1β treatment protects mice against B pseudomallei infection and might be a novel treatment strategy in melioidosis. Lippincott Williams & Wilkins 2016-11 2016-10-17 /pmc/articles/PMC5058638/ /pubmed/27219859 http://dx.doi.org/10.1097/SHK.0000000000000625 Text en Copyright © 2016 by the Shock Society http://creativecommons.org/licenses/by-nc-nd/4.0 This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0
spellingShingle Basic Science Aspects
Weehuizen, Tassili A. F.
Lankelma, Jacqueline M.
De Jong, Hanna K.
De Boer, Onno J.
Roelofs, Joris J. T. H.
Day, Nicholas P.
Gram, Hermann
De Vos, Alex F.
Wiersinga, W. Joost
Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis
title Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis
title_full Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis
title_fullStr Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis
title_full_unstemmed Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis
title_short Therapeutic Administration of a Monoclonal Anti-Il-1β Antibody Protects Against Experimental Melioidosis
title_sort therapeutic administration of a monoclonal anti-il-1β antibody protects against experimental melioidosis
topic Basic Science Aspects
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058638/
https://www.ncbi.nlm.nih.gov/pubmed/27219859
http://dx.doi.org/10.1097/SHK.0000000000000625
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