Inflammasome activation and IL-1 signaling during placental malaria induce poor pregnancy outcomes
Aramys Silva Reis, Renato Barboza, Oscar Murillo, André Barateiro, Erika Paula Machado Peixoto, Flávia Afonso Lima, Vinícius M. Gomes, Jamille Gregório Dombrowski, Vinícius Nunes Cordeiro Leal, Franciele Rodrigues Araújo, Carla Letícia Bandeira, Rosana Beatriz Duque Araujo, Rita Neres, Rodrigo Medeiros de Souza, Fábio Trindade Maranhão Costa, Alessandra Pontillo, Estela Bevilacqua, Carsten Wrenger, Gerhard Wunderlich, Giuseppe Palmisano, Letícia Labriola, Karina Ramalho Bortoluci, Carlos Penha‐Gonçalves, Lígia Antunes Gonçalves, Sabrina Epiphânio, Cláudio Romero Farias Marinho
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-1β (IL-1β) 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-1β-mediated signaling is a determinant of PM pathogenesis, suggesting that IL-1R antagonists can improve clinical outcomes of malaria infection in pregnancy.