Abstract
Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1β. 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-γ-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1β expression required a second stimulation with LPS and was also dependent on IFN-γ-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1β 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 CD14dimCD16+Caspase-1+ monocytes in peripheral blood mononuclear cells from febrile malaria patients. These cells readily produced large amounts of IL-1β 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-1β and hypersensitivity to secondary bacterial infection during malaria.
Highlights
Every year, approximately 250 million people are infected with Plasmodium, contributing to significant social and economic instability in the developing countries around the world [1]
One of the hallmarks of malaria syndrome is the paroxysm, which is characterized by high fever associated with peak of parasitemia
In this study we dissected the mechanisms of induction and the importance of the pyrogenic cytokine, interleukin-1 beta (IL-1b) in the pathogenesis of malaria
Summary
Approximately 250 million people are infected with Plasmodium, contributing to significant social and economic instability in the developing countries around the world [1]. One of the main physiological responses to Plasmodium infection is the paroxysm – characterized by cycles of sharp peaks of high fever accompanied by chills and rigors, which coincide with the release of parasites from synchronized infected red blood cells [2,3]. Parasite components, such as DNA bound to hemozoin [4,5] and glycosylphosphatidylinositol (GPI) anchors [6], trigger the production of proinflammatory cytokines, including interleukin-1 beta (IL-1b), via activation of Toll-Like receptors (TLRs) [7]. The NLRP12 was the first NLR shown to associate with ASC and to form an active
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