Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes, São Paulo, São Paulo, Brazil.
Infect Immun. 2021 Jul 15;89(8):e0080920. doi: 10.1128/IAI.00809-20.
Pregnancy-associated malaria is often associated with adverse pregnancy outcomes. Placental circulatory impairments are an intriguing and unsolved component of malaria pathophysiology. Here, we uncovered a Toll-like receptor 4 (TLR4)-TRIF-endothelin axis that controls trophoblast motility and is linked to fetal protection during infection. In a cohort of 401 pregnancies from northern Brazil, we found that infection during pregnancy reduced expression of endothelin receptor B in syncytiotrophoblasts, while endothelin expression was only affected during acute infection. We further show that quantitative expression of placental endothelin and endothelin receptor B proteins are differentially controlled by maternal and fetal TLR4 alleles. Using murine malaria models, we identified placental autonomous responses to malaria infection mediated by fetally encoded TLR4 that not only controlled placental endothelin gene expression but also correlated with fetal viability protection. assays showed that control of endothelin expression in fetal syncytiotrophoblasts exposed to -infected erythrocytes was dependent on TLR4 via the TRIF pathway but not MyD88 signaling. Time-lapse microscopy in syncytiotrophoblast primary cultures and cell invasion assays demonstrated that ablation of TLR4 or endothelin receptor blockade abrogates trophoblast collective motility and cell migration responses to infected erythrocytes. These results cohesively substantiate the hypothesis that fetal innate immune sensing, namely, the TRL4-TRIF pathway, exerts a fetal protective role during malaria infection by mediating syncytiotrophoblast vasoregulatory responses that counteract placental insufficiency.
妊娠相关疟疾常与不良妊娠结局相关。胎盘循环损伤是疟疾病理生理学中一个有趣但尚未解决的组成部分。在这里，我们发现了一个 Toll 样受体 4（TLR4）-TRIF-内皮素轴，它控制滋养层的运动，并与感染期间的胎儿保护有关。在巴西北部的 401 例妊娠队列中，我们发现妊娠期间的感染会降低合体滋养层中内皮素受体 B 的表达，而内皮素的表达仅在急性感染期间受到影响。我们进一步表明，胎盘内皮素和内皮素受体 B 蛋白的定量表达受母体和胎儿 TLR4 等位基因的差异控制。使用鼠疟模型，我们鉴定了胎盘对疟疾感染的自主反应，这种反应是由胎儿编码的 TLR4 介导的，它不仅控制胎盘内皮素基因的表达，而且与胎儿存活保护相关。 实验表明，暴露于感染红细胞的胎儿合体滋养层中内皮素表达的控制依赖于 TLR4 通过 TRIF 途径，但不依赖于 MyD88 信号。在合体滋养层原代培养物中的延时显微镜检查和细胞侵袭实验表明，TLR4 或内皮素受体的消融会破坏滋养层集体运动和对感染红细胞的细胞迁移反应。这些结果一致证实了这样的假设，即胎儿固有免疫感应，即 TLR4-TRIF 途径，通过调节合体滋养层血管调节反应来发挥胎儿保护作用，从而抵消胎盘功能不全。
