TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria

Renato Barboza,Maria Regina D’Império Lima,Aramys Silva Reis,Gerhard Wunderlich,Wesley Luzetti Fotoran,Fabio Trindade Maranhão Costa,Sabrina Epiphanio,Oscar Javier Murillo,Flávia Afonso Lima,Luis Roberto Sardinha,Claudio Romero Farias Marinho,Erika Paula Machado Peixoto,Carla Letícia Bandeira,Lígia Antunes Gonçalves,José Maria Alvarez,Estela Bevilacqua

doi:10.1038/s41598-017-08299-x

Abstract

Malaria-associate pregnancy has a significant impact on infant morbidity and mortality. The detrimental effects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. Herein we sought to evaluate the effect of Toll-like receptors (TLRs) activation on placental malaria (PM) development by using the Plasmodium berghei NK65GFP infection model. We observed that activation of the innate immune system by parasites leads to PM due to local inflammation. We identified TLR4 activation as the main pathway involved in the inflammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro-inflammatory responses, which resulted in an improved pregnancy outcome. Additionally, a similar result was obtained when infected pregnant mice were treated with IAXO-101, a TLR4/CD14 blocker. Together, this study illustrates the importance of TLR4 signalling for the generation of the severe inflammatory response involved in PM pathogenesis. Therefore, our results implicate that TLR4 blockage could be a potential candidate for therapeutic interventions to reduce malaria-induced pathology both in the mother and the fetus.

Highlights

Malaria-associate pregnancy has a significant impact on infant morbidity and mortality
We identified TLR4 activation as the main pathway involved in the inflammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro-inflammatory responses, which resulted in an improved pregnancy outcome
Using a mouse model for placental malaria infection, our study aimed to evaluate the detrimental effects of the severe inflammatory response via TLR4 signalling in the pathogenesis of malaria during pregnancy

Summary

Introduction

Malaria-associate pregnancy has a significant impact on infant morbidity and mortality. The detrimental effects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. We demonstrated that the adverse placental alterations observed in Plasmodium-infected pregnant mice correlated with MyD88 expression, a key component of the Toll-like receptor (TLR) signalling pathway[8]. Previous reports have evidenced that GPI is recognized both by TLR2 and TLR49, whereas hemozoin, a metabolite derived from the parasite heme detoxification, has been implicated in TLR9 stimulation[10,11,12,13] Several adaptor proteins, such as MyD88, Tirap ( known as Mal), Trif and Tram, mediate TLR activation, which culminates in a pro-inflammatory signalling[14]. We wanted to assess if treatment of infected pregnant mice with a TLR4 blocker can reverse the placental damage induced by the malarial infection

Methods

Results

Conclusion