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Inflammasome activation and IL-1 signaling during placental malaria induce poor pregnancy outcomes.

ABSTRACT: Placental malaria (PM) is associated with severe inflammation leading to abortion, preterm delivery, and intrauterine growth restriction. Innate immunity responses play critical roles, but the mechanisms underlying placental immunopathology are still unclear. Here, we investigated the role of inflammasome activation in PM by scrutinizing human placenta samples from an endemic area and ablating inflammasome components in a PM mouse model. The reduction in birth weight in babies from infected mothers is paralleled by increased placental expression of AIM2 and NLRP3 inflammasomes. Using genetic dissection, we reveal that inflammasome activation pathways are involved in the production and detrimental action of interleukin-1? (IL-1?) in the infected placenta. The IL-1R pharmacological antagonist Anakinra improved pregnancy outcomes by restoring fetal growth and reducing resorption in an experimental model. These findings unveil that IL-1?-mediated signaling is a determinant of PM pathogenesis, suggesting that IL-1R antagonists can improve clinical outcomes of malaria infection in pregnancy.

SUBMITTER: Reis AS

PROVIDER: S-EPMC7056302 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Inflammasome activation and IL-1 signaling during placental malaria induce poor pregnancy outcomes.

Reis Aramys S AS Reis Aramys S AS Barboza Renato R Murillo Oscar O Barateiro André A Peixoto Erika P M EPM Lima Flávia A FA Gomes Vinícius M VM Dombrowski Jamille G JG Leal Vinícius N C VNC Araujo Franciele F Bandeira Carla L CL Araujo Rosana B D RBD Neres Rita R Souza Rodrigo M RM Costa Fabio T M FTM Pontillo Alessandra A Bevilacqua Estela E Wrenger Carsten C Wunderlich Gerhard G Palmisano Giuseppe G Labriola Leticia L Bortoluci Karina R KR Penha-Gonçalves Carlos C Gonçalves Lígia A LA Epiphanio Sabrina S Marinho Claudio R F CRF

Science advances 20200304 10

Placental malaria (PM) is associated with severe inflammation leading to abortion, preterm delivery, and intrauterine growth restriction. Innate immunity responses play critical roles, but the mechanisms underlying placental immunopathology are still unclear. Here, we investigated the role of inflammasome activation in PM by scrutinizing human placenta samples from an endemic area and ablating inflammasome components in a PM mouse model. The reduction in birth weight in babies from infected moth ...[more]

PMID: 32181339

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Project description:The bacterial pathogen Listeria monocytogenes breaches the placental barrier and infects the placental/fetal unit resulting in poor pregnancy outcomes. L. monocytogenes is thought to enter the placenta by infection of trophoblasts at the maternal/fetal interface. Trophoblasts are fetal epithelial cells that delineate the maternal/fetal interface and ensure critical functions by promoting all nutritional and waste exchanges between maternal and fetal bloods and by forming a protective immune barrier. In this work, we report the first transcriptomic analysis of L. monocytogenes-infected trophoblasts by RNA sequencing. Primary human trophoblasts (PHT) and BeWo (fused and non-fused) were infected for 5 h with WT L. monocytogenes and highly purified RNA was extracted from infected and control cells. A 200 ng total RNA sample was used for sequencing on Illumina NovaSeq SP flowcell in paired-end 150 bp format to a read yield between 70-80 million reads. Pathway analysis showed that infection upregulated TLR2-, NOD-like, and cytosolic DNA sensing pathways, as well as downstream pro-inflammatory circuitry (NF-KB, AP-1, IRF4, IRF7) leading to the production of mediators known to elicit the recruitment and activation of maternal leukocytes (IL8, IL6, TNFA, MIP-1). Signature genes associated with poor pregnancy outcomes were also upregulated upon infection. Measuring the release of 54 inflammatory mediators confirmed the transcriptomic data and revealed sustained production of tolerogenic factors (IL-27, IL-10, IL-1RA, TSLP) despite infection. Both the SYN and mononuclear trophoblasts produced cytokines, but surprisingly, some cytokines were predominantly produced by the SYN (IL-8, IL-6) or by non-fused trophoblasts (TNFA). Collectively, our data support that trophoblasts act as placental gatekeepers that limit and detect L. monocytogenes infection resulting in a pro-inflammatory response, which may contribute to the poor pregnancy outcomes if the pathogen persists.

Dataset Information

Inflammasome activation and IL-1 signaling during placental malaria induce poor pregnancy outcomes.

Publications

Inflammasome activation and IL-1 signaling during placental malaria induce poor pregnancy outcomes.

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