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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-1?. 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-?-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1? expression required a second stimulation with LPS and was also dependent on IFN-?-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1? 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-1? 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-1? and hypersensitivity to secondary bacterial infection during malaria.

SUBMITTER: Ataide MA

PROVIDER: S-EPMC3894209 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.

Ataide Marco A MA Andrade Warrison A WA Zamboni Dario S DS Wang Donghai D Souza Maria do Carmo Mdo C Franklin Bernardo S BS Elian Samir S Martins Flaviano S FS Pereira Dhelio D Reed George G Fitzgerald Katherine A KA Golenbock Douglas T DT Gazzinelli Ricardo T RT

PLoS pathogens 20140116 1

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 ...[more]

PMID: 24453977

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Project description:The crosstalk between the host's inflammasome system and the invading virulent/less-virulent viruses determines the outcome of the ensuing inflammatory response. An appropriate activation of inflammasomes triggers antiviral inflammatory responses that clear the virus and heal the inflamed tissue. However, an aberrant activation of inflammasomes can result in a harmful and overwhelming inflammation that could damage the infected tissue. The underlying host's immune mechanisms and the viral virulent factors that impact severe clinical inflammatory disease remain to be fully elucidated. In this study, we used herpes simplex virus type 1 (HSV-1), the causative agent of corneal inflammatory herpetic disease, as a model pathogen to determine: (i) Whether and how the virulence of a virus affects the type and the activation level of the inflammasomes; and (ii) How triggering specific inflammasomes translates into protective or damaging inflammatory response. We showed that, in contrast to the less-virulent HSV-1 strains (RE, F, KOS, and KOS63), corneal infection of B6 mice with the virulent HSV-1 strains (McKrae, 17 or KOS79): (i) Induced simultaneous expression of the NLRP3, NLRP12, and IFI16 inflammasomes; (ii) Increased production of the biologically active Caspase-1 and pro-inflammatory cytokines IL-1β and IL-18; (iii) Heightened recruitment into the inflamed cornea of CD45highLy6C+Ly6G-F4/80+CD11b+CD11c- inflammatory monocytes and CD45highCD11b+F4/80-Ly6GhiLy6Cmed neutrophils; and (iv) This intensified inflammatory response was associated with a severe corneal herpetic disease, irrespective of the level of virus replication in the cornea. Similarly, in vitro infection of human corneal epithelial cells and human monocytic THP-1 cells with the virulent HSV-1 strains triggered a synchronized early expression of NLRP3, NLRP12 and IFI16, 2 h post-infection, associated with formation of single and dense specks of the adapter molecule ASC in HSV(+) cells, but not in the neighboring bystander HSV(-) cells. This was associated with increased cleavages of Caspase-1, IL-1β, and IL-18. These findings suggest a previously unappreciated role of viral virulence in a synchronized early induction of the NLRP3, NLRP12, and IFI16 inflammasomes that lead to a damaging inflammatory response. A potential role of common virus virulent factors that stimulate this harmful inflammatory corneal disease is currently under investigation.

Dataset Information

Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.

Publications

Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.

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