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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: Infection and Immunity; v. 89, n. 8 AUG 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 19/12068-5 - Identification of predictive biomarkers of placental dysfunction in Malaria
• Grantee: Jamille Gregório Dombrowski
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/07030-0 - Characterization of autophagic activity and inflammasome in placental malaria
• Grantee: Cláudio Romero Farias Marinho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/04755-3 - Association of gestational malaria with intrauterine growth restriction and low birth weight in the far-western Brazilian Amazon
• Grantee: Jamille Gregório Dombrowski
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/09964-5 - The role of inflammasomes in the pathogenesis of malaria during pregnancy: effects and mechanisms
• Grantee: Cláudio Romero Farias Marinho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/03939-7 - Impact of autophagy and inflammasome on the pathogenesis of Placental Malaria
• Grantee: André Filipe Rivais Martins Barateiro
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 20/06747-4 - Study of the humoral immune response in recurrent infections by Plasmodium vivax in pregnant women from Amazon region
• Grantee: Cláudio Romero Farias Marinho
• Support Opportunities: Regular Research Grants