Department of Medicine, Division of Infectious Diseases and Immunology
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
Ataide, Marco A.; Andrade, Warrison A.; Zamboni, Dario S.; Wang, Donghai; Souza, Maria do Carmo; Franklin, Bernardo S.; Elian, Samir; Martins, Flaviano S.; Pereira, Dhelio; Reed, George W.; Fitzgerald, Katherine A.; Golenbock, Douglas T.; and Gazzinelli, Ricardo T., "Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection" (2014). Infectious Diseases and Immunology Publications and Presentations. 189.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.