TLR4-Endothelin Axis Controls Syncytiotrophoblast Motility and Confers Fetal Protection in Placental Malaria

Autor(es)

Pandya, Yash ^{[1, 2]} ; Marta, Alexander ^[1] ; Barateiro, Andre ^[3] ; Bandeira, Carla Leticia ^[3] ; Dombrowski, Jamille Gregorio ^[3] ; Costa, Joao ^[1] ; Farias Marinho, Claudio Romero ^[3] ; Penha-Goncalves, Carlos ^[1]

Afiliação do(s) autor(es)

^[1] Inst Gulbenkian Ciencias, Oeiras - Portugal

^[2] Inst Med Mol, Av Prof Egas Moniz, Lisbon - Portugal

^[3] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Av Prof Lineu Prestes, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Infection and Immunity; v. 89, n. 8 AUG 2021.
• Citações Web of Science: 0

Resumo

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 Plasmodium 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. In vitro assays showed that control of endothelin expression in fetal syncytiotrophoblasts exposed to Plasmodium-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. (AU)

• Processo FAPESP: 19/12068-5 - Identificação de biomarcadores preditivos de disfunção placentária na Malária
• Beneficiário: Jamille Gregório Dombrowski
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/07030-0 - Caracterização da atividade autofágica e de inflamassoma na malária placentária
• Beneficiário: Cláudio Romero Farias Marinho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/04755-3 - Associação entre malária gestacional, restrição do crescimento intrauterino e baixo peso ao nascer na Amazônia Extremo-Ocidental Brasileira
• Beneficiário: Jamille Gregório Dombrowski
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 14/09964-5 - O papel dos inflamassomas na patogênese da malária associada à gravidez: efeitos e mecanismos
• Beneficiário: Cláudio Romero Farias Marinho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/03939-7 - Impacto da autofagia e do inflamassoma na patogênese da Malária Placentária
• Beneficiário: André Filipe Rivais Martins Barateiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 20/06747-4 - Estudo da resposta imune humoral nas infecções recorrentes por Plasmodium vivax em gestantes da região amazônica
• Beneficiário: Cláudio Romero Farias Marinho
• Modalidade de apoio: Auxílio à Pesquisa - Regular