RESUMEN

Introduction: Controlling the invasive activity of trophoblastic tissue has not been elucidated. In the accreta placenta, the invasion of placental tissue is directly related to the expression of CRIPTO-1 at the maternal-fetal interface. The aim of this study is to evaluate if the expression of the CRIPTO-1 is related to different degrees of trophoblast invasion into the tube wall in ampullary pregnancy. Methods: Prospective study with 21 patients with ampullary tubal pregnancy undergoing salpingectomy. Anatomopathological evaluation determined the degree of invasion of trophoblast tissues into the tubal wall and grouped the samples into invasive degrees I, II, or III. The groups were compared for tissue expression of CRIPTO-1 using the Kruskal-Wallis nonparametric test. p values lower than 0.05 were considered significant. Results: Quantitative expression of CRIPTO-1 differed in each of the three groups of trophoblast invasion in the tubal wall in ampullary pregnancies (p < 0.001). There is a difference between groups when grade I + grade II versus grade III (p < 0.001) and grade I versus grade II + grade III (p < 0.001). The tissue expression of CRIPTO-1 in ectopic trophoblasts showed that deeper invasion of the tubal wall was associated with stronger expression than in shallow invasion (p < 0.001). Discussion. In ampullary pregnancies, the depth of penetration of trophoblast tissue in the tubal wall is related to CRIPTO-1 tissue expression.

Asunto(s)

Embarazo Tubario , Trofoblastos , Trompas Uterinas/metabolismo , Femenino , Proteínas Ligadas a GPI , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de Neoplasias , Placenta/metabolismo , Embarazo , Embarazo Tubario/metabolismo , Embarazo Tubario/patología , Estudios Prospectivos , Trofoblastos/metabolismo

RESUMEN

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.

Asunto(s)

Endotelinas/metabolismo , Placenta/metabolismo , Placenta/parasitología , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Trofoblastos/metabolismo , Biomarcadores , Brasil , Femenino , Interacciones Huésped-Patógeno/inmunología , Humanos , Malaria/inmunología , Malaria/metabolismo , Malaria/parasitología , Placenta/inmunología , Embarazo , Complicaciones Parasitarias del Embarazo , Resultado del Embarazo

RESUMEN

Importance: Malaria during pregnancy is associated with adverse events for the fetus and newborn, but the association of malaria during pregnancy with the head circumference of the newborn is unclear. Objective: To investigate the association of malaria during pregnancy with fetal head growth. Design, Setting, and Participants: Two cohort studies were conducted at the general maternity hospital of Cruzeiro do Sul (Acre, Brazil) in the Amazonian region. One cohort study prospectively enrolled noninfected and malaria-infected pregnant women who were followed up until delivery, between January 2013 and April 2015. The other cohort study was assembled retrospectively using clinical and malaria data from all deliveries that occurred between January 2012 and December 2013. Data analyses were conducted from January to August 2017 and revised in November 2018. Clinical data from pregnant women and anthropometric measures of their newborns were evaluated. A total of 600 pregnant women were enrolled through volunteer sampling (prospective cohort study), and 4697 pregnant women were selected by population-based sampling (retrospective cohort study). After application of exclusion criteria, data from 251 (prospective cohort study) and 232 (retrospective cohort study) malaria-infected and 158 (prospective cohort study) and 3650 (retrospective cohort study) noninfected women were evaluated. Exposure: Malaria during pregnancy. Main Outcomes and Measures: The primary end point was the incidence of altered head circumference in newborns delivered from malaria-infected mothers compared with that from noninfected mothers. Secondary end points included measures of placental pathology relative to newborn head circumference. Results: In total, 4291 maternal-child pairs were analyzed. Among 409 newborns in the prospective cohort study, the mothers of 251 newborns had malaria during pregnancy, infected with Plasmodium vivax, Plasmodium falciparum, or both. Among 3882 newborns in the retrospective cohort study, 232 were born from mothers that had malaria during pregnancy. The prevalence of newborns with a small head (19 [30.7%] in the prospective cohort study and 30 [36.6%] in the retrospective cohort study) and the prevalence of microcephaly among newborns (5 [8.1%] in the prospective cohort study and 6 [7.3%] in the retrospective cohort study) were higher among newborns from women infected with P falciparum during pregnancy. Multivariate logistic regression analyses revealed that P falciparum infection during pregnancy represented a significant risk factor for the occurrence of small head circumference in newborns (prospective cohort study: odds ratio, 3.15; 95% CI, 1.52-6.53; P = .002; retrospective cohort study: odds ratio, 1.91; 95% CI, 1.21-3.04; P = .006). Placental pathologic findings corroborated this association, with more syncytial nuclear aggregates and inflammatory infiltrates occurring in placentas of newborns born with decreased head circumference. Conclusions and Relevance: This study indicates that falciparum malaria during pregnancy is associated with decreased head circumference in newborns, which is in turn associated with evidence of placental malaria.

Asunto(s)

Cabeza/anatomía & histología , Malaria Falciparum/fisiopatología , Exposición Materna/efectos adversos , Complicaciones Infecciosas del Embarazo/epidemiología , Adulto , Brasil/epidemiología , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Embarazo , Prevalencia , Estudios Prospectivos , Estudios Retrospectivos

RESUMEN

Malaria in pregnancy is a public health concern in malaria-endemic areas. Accumulation of maternal immune cells in the placenta and increased levels of inflammatory cytokines caused by sequestration of Plasmodium falciparum-infected erythrocytes have been associated to poor neonatal outcomes, including low birth weight because of fetal growth restriction. Little is known about the molecular changes occurring in a P. falciparum-infected placenta that has developed placental malaria during pregnancy but had the parasites cleared by pharmacological treatment (past infection). We conducted an integrated proteome, phosphoproteome and glycoproteome analysis in past P. falciparum-infected placentas aiming to find molecular changes associated with placental malaria. A total of 2946 proteins, 1733 N-linked glycosites and 4100 phosphosites were identified and quantified in this study, disclosing overrepresented processes related to oxidative stress, protein folding and regulation of apoptosis in past-infected placentas Moreover, AKT and ERK signaling pathways activation, together with clinical data, were further correlated to an increased apoptosis in past-infected placentas. This study showed apoptosis-related mechanisms associated with placental malaria that can be further explored as therapeutic target against adverse pregnancy outcomes.

Asunto(s)

Malaria Falciparum/metabolismo , Placenta/metabolismo , Complicaciones Parasitarias del Embarazo/metabolismo , Proteómica/métodos , Animales , Modelos Animales de Enfermedad , Femenino , Glicosilación , Humanos , Sistema de Señalización de MAP Quinasas , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones , Fosforilación , Placenta/parasitología , Embarazo , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Mapas de Interacción de Proteínas

RESUMEN

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

RESUMEN

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 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.

Asunto(s)

Malaria/metabolismo , Placenta/metabolismo , Complicaciones Infecciosas del Embarazo/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Femenino , Feto/metabolismo , Feto/parasitología , Interacciones Huésped-Parásitos/efectos de los fármacos , Malaria/genética , Malaria/parasitología , Ratones Endogámicos C57BL , Ratones Noqueados , Placenta/parasitología , Plasmodium berghei/fisiología , Embarazo , Complicaciones Infecciosas del Embarazo/genética , Complicaciones Infecciosas del Embarazo/parasitología , Resultado del Embarazo , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética

RESUMEN

CRIPTO-(CR)1 is a protein associated with tumorigenesis and metastasis. Here we demonstrate that CR-1 expression in normal and creta placentas is associated with various degrees of uterine invasion. Cytokeratin (CK) and CR-1 protein expression was visualized by immunohistochemical staining of formalin-fixed, paraffin-embedded placental specimens (control placentas, n = 9; accreta, n = 6; increta, n = 10; percreta, n = 15). The pattern of extravillous trophoblast (EVT) cell morphology was distinctive in creta placentas: densely-compacted cell columns and large star-shaped cells with a typically migratory phenotype, not common among third trimester control placentas. Quantification revealed higher CR-1 immunoreactivities in accreta (P = 0.001), increta (P = 0.0002), and percreta placentas (P = 0.001) than in controls. In contrast to controls, there was a significant positive relationship between CR-1 and CK reactivity in all creta placentas (accreta, P = 0.02; increta, P = 0.0001, and percreta, P = 0.025). This study demonstrated CR-1 expression in the placental bed, its increased expression in creta placentas, and EVT cells as the main CR-1-producing cell type. Morphological examination revealed an immature and invasive trophoblast profile in creta placentas, suggesting impairment of the trophoblast differentiation pathway. These findings provide important new insights into the pathophysiology of abnormal creta placentation and its gestational consequences.

Asunto(s)

Proteínas Ligadas a GPI/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Proteínas de Neoplasias/biosíntesis , Tercer Trimestre del Embarazo/metabolismo , Embarazo/metabolismo , Trofoblastos/citología , Trofoblastos/metabolismo , Adulto , Femenino , Humanos , Inmunohistoquímica