Contribution of inflammasome genetics in Plasmodium vivax malaria Marina L.S. Santos a , Edione Cristina Reis b , Pamela N. Bricher b , Tais N. Sousa a , Cristiana F.A. Brito a , Marcus V.G. Lacerda c , Cor J.F. Fontes d , Luzia H. Carvalho a , Alessandra Pontillo b, ⁎ a Laboratório de Malária, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil b Laboratório de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil c Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Instituto de Pesquisas Leônidas and Maria Deane, Fundação Oswaldo Cruz, Manaus, AM, Brazil d Hospital Julio Muller, Universidade Federal de Mato Grosso, Cuiabá, MT, Brazil abstract article info Article history: Received 1 December 2015 Received in revised form 26 February 2016 Accepted 28 February 2016 Available online 3 March 2016 Recent reports showed that, in mice, symptomatic Plasmodium infection triggers NLRP3/NLRP12-dependent inflammasome formation and caspase-1 activation in monocytes. In humans, few works demonstrated that inflammasome is activated in malaria. As Plasmodium vivax is a potent inducer of inflammatory response we hypothesised that inflammasome genetics might affect P. vivax malaria clinical presentation. For this purpose, se- lected SNPs in inflammasome genes were analysed among patients with symptomatic P. vivax malaria. 157 Brazilian Amazon patients with P. vivax malaria were genotyped for 10 single nucleotide polymorphisms (SNPs) in inflammasome genes NLRP1, NLRP3, AIM2, CARD8, IL1B, IL18 and MEFV. Effect of SNPs on hematologic and clinical parameters was analysed by multivariate analysis. Our data suggested an important role of NLRP1 inflammasome receptor in shaping the clinical presentation of P. vivax malaria, in term of presence of fever, anaemia and thrombocytopenia. Moreover IL1B rs1143634 resulted significantly associated to patients' parasitaemia, while IL18 rs5744256 plays a protective role against the devel- opment of anaemia. Polymorphisms in inflammasome genes could affect one or other aspects of malaria pathogenesis. Moreover, these data reveal novel aspects of P. vivax/host interaction that involved NLRP1-inflammasome. © 2016 Elsevier B.V. All rights reserved. Keywords: Inflammasome NLRP1 NLRP3 IL1B IL18 P. vivax Malaria 1. Background Malaria remains a major public health problem worldwide, with 3.2 billion people at risk of being infected and developing the disease (WHO, 2015). Among the five Plasmodium species that cause malaria in humans, Plasmodium falciparum has been considered the main cause of severe and fatal disease, while P. vivax is a major cause of mor- bidity outside Africa and has also been associated with clinical severity and systemic inflammation (Barber et al., 2015). A central mechanism for inflammation induction is the secretion of pro-inflammatory cytokines IL-1ß e IL-18 from innate immune cells. IL-1ß e IL-18 liberation depends on the activation of a cytoplasmic com- plex, known as inflammasome. Several intracellular Pattern Recognition Receptors (PRRs) belonging to NLR family (i.e.: NLRP1, NLRP3, NLRP12) and to other protein families (i.e.: AIM2 or pyrin/MEFV), are able to in- duce the inflammasome assembling in response to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Upon recognition of PAMPs and/or DAMPs, the receptor recruits the adaptor protein ASC and the cysteine-aspartic protease caspase-1, which is responsible for the processing of pro-IL-1ß and pro-IL-18 (Man and Kanneganti, 2015). Recent reports showed that, in mice, symptomatic Plasmodium in- fection triggers NLRP3/NLRP12-dependent inflammasome formation and caspase-1 activation in monocytes, leading to dramatic IL-1ß secre- tion especially when exposed to a second microbial challenge (Ataide et al., 2014). Furthermore hemozoin and DNA activated inflammasome through NLRP3 and AIM2 receptors respectively, in murine infected erythrocytes (Kalantari et al., 2014). In humans, few works demonstrated that inflammasome is activat- ed in malaria. In P. falciparum, for example, the opsonization of malaria-infected erythrocytes activates the inflammasome and leads to FcR-mediated phagocytosis in macrophages (Zhou et al., 2012). On the other hand, the presence of inflammasome complexes was demon- strated in monocytes from malaria patients containing either NLRP3 or NLRP12 inflammasomes (Ataide et al., 2014). Although multiple studies have revealed that malaria has been a major force of evolutionary selection on the human genome (reviewed in (Malaria Genomic Epidemiology, 2014) little is currently known about the effects of malaria on the evolution of the human immune genes, possibly because the phenotypic consequences are more subtle than those of the classic erythrocyte variants (Kwiatkowski, 2005). Infection, Genetics and Evolution 40 (2016) 162–166 ⁎ Corresponding author at: Laboratório de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas, Avenida Prof. Lineu Prestes, 1730, Cidade Universitária, São Paulo, SP, Brazil. E-mail address: alepontillo@usp.br (A. Pontillo). http://dx.doi.org/10.1016/j.meegid.2016.02.038 1567-1348/© 2016 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Infection, Genetics and Evolution journal homepage: www.elsevier.com/locate/meegid