TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria 

Sci Rep. 7:8623 (2017). Barboza R1, Lima FA2, Reis AS2, Murillo OJ2, Peixoto EPM2, Bandeira CL2, Fotoran WL2, Sardinha LR3, Wunderlich G2, Bevilacqua E4, Lima MRD5, Alvarez JM5, Costa FTM6, Gonçalves LA2, Epiphanio S7, Marinho CRF8.


Malaria-associated 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.