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TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria.

ABSTRACT: 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.

SUBMITTER: Barboza R

PROVIDER: S-EPMC5561130 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria.

Barboza Renato R Lima Flávia Afonso FA Reis Aramys Silva AS Murillo Oscar Javier OJ Peixoto Erika Paula Machado EPM Bandeira Carla Letícia CL Fotoran Wesley Luzetti WL Sardinha Luis Roberto LR Wunderlich Gerhard G Bevilacqua Estela E Lima Maria Regina D'Império MRD Alvarez José Maria JM Costa Fabio Trindade Maranhão FTM Gonçalves Lígia Antunes LA Epiphanio Sabrina S Marinho Claudio Romero Farias CRF

Scientific reports 20170817 1

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<sup>GFP</sup> infection model. We observed that activation of the innate immune system by parasites leads to PM due t ...[more]

PMID: 28819109

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Project description:ObjectiveCurrently, no investigations reliably identify placental dysfunction in late pregnancy. To facilitate the development of such investigations we aimed to identify placental features that differ between normal and adverse outcome in late pregnancy in a group of pregnancies with reduced fetal movement.MethodsFollowing third trimester presentation with reduced fetal movement (N = 100), placental structure ex vivo was measured. Placental function was then assessed in terms of (i) chorionic plate artery agonist responses and length-tension characteristics using wire myography and (ii) production and release of placentally derived hormones (by quantitative polymerase chain reaction and enzyme linked immunosorbant assay of villous tissue and explant conditioned culture medium).ResultsPlacentas from pregnancies ending in adverse outcome (N = 23) were ~25% smaller in weight, volume, length, width and disc area (all p<0.0001) compared with those from normal outcome pregnancies. Villous and trophoblast areas were unchanged, but villous vascularity was reduced (median (interquartile range): adverse outcome 10 (10-12) vessels/mm2 vs. normal outcome 13 (12-15), p = 0.002). Adverse outcome pregnancy placental arteries were relatively insensitive to nitric oxide donated by sodium nitroprusside compared to normal outcome pregnancy placental arteries (50% Effective Concentration 30 (19-50) nM vs. 12 (6-24), p = 0.02). Adverse outcome pregnancy placental tissue contained less human chorionic gonadotrophin (20 (11-50) vs. 55 (24-102) mIU/mg, p = 0.007) and human placental lactogen (11 (6-14) vs. 27 (9-50) mg/mg, p = 0.006) and released more soluble fms-like tyrosine kinase-1 (21 (13-29) vs. 5 (2-15) ng/mg, p = 0.01) compared with normal outcome pregnancy placental tissue.ConclusionThese data provide a description of the placental phenotype of adverse outcome in late pregnancy. Antenatal tests that accurately reflect elements of this phenotype may improve its prediction.

Project description:BACKGROUND: The placenta plays a crucial role during pregnancy for growth and development of the fetus. Less than optimal placental performance may result in morbidity or even mortality of both mother and fetus. Awareness among pediatricians, however, of the benefit of placental findings for neonatal care, is limited. OBJECTIVES: To provide a systematic overview of the relation between placental lesions and neonatal outcome. DATA SOURCES: Pubmed database, reference lists of selected publications and important research groups in the field. STUDY APPRAISAL AND SYNTHESIS METHODS: We systematically searched the Pubmed database for literature on the relation between placental lesions and fetal and neonatal mortality, neonatal morbidity and neurological outcome. We conducted three separate searches starting with a search for placental pathology and fetal and neonatal mortality, followed by placental pathology and neonatal morbidity, and finally placental pathology and neurological development. We limited our search to full-text articles published in English from January 1995 to October 2013. We refined our search results by selecting the appropriate articles from the ones found during the initial searches. The first selection was based on the title, the second on the abstract, and the third on the full article. The quality of the selected articles was determined by using the Newcastle-Ottawa Quality Assessment Scale. RESULTS: Placental lesions are one of the main causes of fetal death, where placental lesions consistent with maternal vascular underperfusion are most important. Several neonatal problems are also associated with placental lesions, whereby ascending intrauterine infection (with a fetal component) and fetal thrombotic vasculopathy constitute the greatest problem. CONCLUSIONS: The placenta plays a key role in fetal and neonatal mortality, morbidity, and outcome. Pediatricians should make an effort to obtain the results of placental examinations.

Dataset Information

TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria.

Publications

TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria.

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