UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date

1-16-2014

Document Type

Article

Disciplines

Bacteria | Bacterial Infections and Mycoses | Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease | Parasitic Diseases

Abstract

Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1beta. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-gamma-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1beta expression required a second stimulation with LPS and was also dependent on IFN-gamma-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1beta upon a second microbial stimulus, and became hypersensitive to septic shock. Therapeutic intervention with IL-1 receptor antagonist prevented bacterial-induced lethality in rodents. Similar to mice, we observed a significantly increased frequency of circulating CD14(+)CD16(-)Caspase-1(+) and CD14(dim)CD16(+)Caspase-1(+) monocytes in peripheral blood mononuclear cells from febrile malaria patients. These cells readily produced large amounts of IL-1beta after stimulation with LPS. Furthermore, we observed the presence of inflammasome complexes in monocytes from malaria patients containing either NLRP3 or NLRP12 pyroptosomes. We conclude that NLRP12/NLRP3-dependent activation of caspase-1 is likely to be a key event in mediating systemic production of IL-1beta and hypersensitivity to secondary bacterial infection during malaria.

Rights and Permissions

Citation: PLoS Pathog. 2014 Jan;10(1):e1003885. doi: 10.1371/journal.ppat.1003885. Epub 2014 Jan 16. Link to article on publisher's site

Journal/Book/Conference Title

PLoS pathogens

Comments

© 2014 Ataide et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Related Resources

Link to Article in PubMed

PubMed ID

24453977

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

 
 

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