Malaria-Induced NLRP12/NLRP3-Dependent Caspase-1 Activation Mediates Inflammation and Hypersensitivity to Bacterial Superinfection

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.

Hemolysis-induced lethality involves inflammasome activation by heme

“…These results add a component of the innate immune system to the recently demonstrated essential participation of heme-induced TLR4 activation in sickle cell disease (29,30). Moreover, inflammasome activation is likely important in malaria pathogenesis (45,66). Thus, understanding the molecular signaling pathways affected by heme might prove useful to the identification of new options for treating pathological conditions that have increased extracellular heme.…”

Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4 + T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

“…Pyroptosis involves caspases-1, -4, and -5 and is inherently proinflammatory, whereas apoptosis involves caspase-2, -3, -6, -7, -8, -9, and -10 and occurs in the absence of inflammation (20). Although extensively studied in bacterial infections (21,22), the roles of pyroptosis in viral infections were just recently recognized (14,23). While the elegant ex vivo study demonstrated that pyroptosis induced by abortive HIV-1 infection is the predominant means of CD4 ϩ T cell depletion in HIV-1 infection (14), the in vivo role of pyroptosis in CD4 ϩ T cell death in HIV-1/simian immunodeficiency virus (SIV) infection, especially in very early infection, remains largely unknown.…”

Inflamosomes as Activated Molecular Platform for Engagement of Innate Immune Defences

“…It was also involved in caspase-1 activation in response to Yersinia pestis and Plasmodium infection (Vladimer et al, 2012;Ataide et al, 2014). The role of NLRP12 in NF-κB-mediated signaling makes it an important regulator of immune response after Salmonella infection and during colorectal cancer (Zaki et al, 2014) AIM 2 inflammasome AIM 2 (absent in melanoma 2) is a cytosolic dsDNA sensing inflammasome activated by bacterial, viral, and mammalian host DNA to trigger caspase-1 activation (Nakahira et al, 2011).…”