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

PLoS Pathogens

Ricardo T. Gazzinelli¹  Warrison A. Andrade²  Maria do Carmo Souza²  Katherine A. Fitzgerald³  Douglas T. Golenbock³  Dario S. Zamboni⁴  Flaviano S. Martins⁴  Bernardo S. Franklin⁴  Dhelio Pereira⁵  Samir Elian⁵  George Reed⁶  Donghai Wang⁶  Marco A. Ataide⁶ 

[1] Centro de Pesquisas em Medicina Tropical, Porto Velho, Rondônia, Brazil;Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil;Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil;Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America;Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil;Laboratório de Imunopatologia, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil

关键词: Malaria;    Plasmodium;    Inflammasomes;    Parasitic diseases;    Monocytes;    Cytokines;    Sepsis;    Lethality (bacteriology);   

DOI  :  10.1371/journal.ppat.1003885

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY