TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria

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 NK65(GFP) 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.Fundação de Amparo a Pesquisa do Estado de São Paulo - FAPESPCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESConselho Nacional de Desenvolvimento Científico e Tecnológico - CNPqUniv Fed São Paulo, Dept Ciencias Biol, Diadema, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Parasitol, São Paulo, BrazilHosp Israelita Albert Einstein, São Paulo, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolvimento, São Paulo, BrazilUniv Estadual Campinas, Dept Genet Evolucao & Bioagentes, Inst Biol, Campinas, SP, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Imunol, São Paulo, BrazilUniv São Paulo, Dept Analises Clin & Toxicol, Fac Ciencias Farmaceut, São Paulo, BrazilUniv Fed São Paulo, Dept Ciencias Biol, Diadema, BrazilFAPESP: 2009/53889-0FAPESP: 2014/09964-5FAPESP: 2014/20451-0FAPESP: 2012/16525-2FAPESP: 2011/17880-8FAPESP: 2013/16417-8FAPESP: 2011/19048-8FAPESP: 2013/00981-1FAPESP: 2015/06106-0]CAPES: AUX-PE-PNPD 2751/2010CNPq: 475771/2009-5Web of Scienc

TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria (vol 7, 2017)

Malaria-associate pregnancy has a signifcant impact on infant morbidity and mortality. The detrimental efects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. Herein we sought to evaluate the efect 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 infammation. We identifed TLR4 activation as the main pathway involved in the infammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro-infammatory 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 infammatory 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.Univ Fed Sao Paulo, Dept Ciencias Biol, Diadema, BrazilUniv Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Sao Paulo, BrazilHosp Israelita Albert Einstein, Sao Paulo, BrazilUniv Sao Paulo, Dept Biol Celular & Desenvolvimento, Sao Paulo, BrazilUniv Estadual Campinas, Inst Biol, Dept Genet Evolucao & Bioagentes, Campinas, SP, BrazilUniv Sao Paulo, Inst Ciencias Biomed, Dept Imunol, Sao Paulo, BrazilUniv Sao aulo, Fac Ciencias Farmaceut, Dept Anal Clin & Toxicol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Ciencias Biol, Diadema, BrazilWeb of Scienc