{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T13:58:17Z","timestamp":1778853497507,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,10]],"date-time":"2024-08-10T00:00:00Z","timestamp":1723248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sistema general de regal\u00edas (SGR)","award":["BPIN 2020000100523"],"award-info":[{"award-number":["BPIN 2020000100523"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Malaria during pregnancy has been associated with significant risks to both the mother and the fetus, leading to complications such as anemia, low birth weight, and increased infant mortality. The trophoblast cells, a key component of the placenta, are crucial for nutrient and oxygen exchange between mother and fetus. The differentiation of cytotrophoblasts (CTBs) into syncytiotrophoblasts (STBs) is critical for proper pregnancy development. These cells form the bi-stratified epithelium surrounding the placental villi. While previous studies have described an inflammatory activation of STB cells exposed to Plasmodium falciparum-infected erythrocytes (P. falciparum-IE) or components such as hemozoin (HZ), little is known about the direct effect this parasite may have on the epithelial turnover and function of trophoblast cells. This study aims to contribute to understanding mechanisms leading to placental damage during placental malaria using a BeWo cell line as a differentiation model. It was found that P. falciparum-IE interferes with the fusion of BeWo cells, affecting the differentiation process of trophoblast. A reduction in syncytialization could be associated with the adverse effects of infection in fetal health, altering the remodeling of the trophoblast epithelial barrier and reducing their capacity to exchange substances. However, further studies are necessary to assess alterations in the functionality of this epithelium.<\/jats:p>","DOI":"10.3390\/microorganisms12081640","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T05:19:38Z","timestamp":1723439978000},"page":"1640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Alteration of Trophoblast Syncytialization by Plasmodium falciparum-Infected Erythrocytes"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8734-7637","authenticated-orcid":false,"given":"Carolina","family":"L\u00f3pez-Guzm\u00e1n","sequence":"first","affiliation":[{"name":"Grupo Malaria, Facultad de Medicina, Universidad de Antioquia, Calle 62 #52-59, Torre 1, Laboratorio 610, Medellin 050001, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8265-0133","authenticated-orcid":false,"given":"Ana Mar\u00eda","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Grupo Malaria, Facultad de Medicina, Universidad de Antioquia, Calle 62 #52-59, Torre 1, Laboratorio 610, Medellin 050001, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-3298","authenticated-orcid":false,"given":"Ana Mar\u00eda","family":"V\u00e1squez","sequence":"additional","affiliation":[{"name":"Grupo Malaria, Facultad de Medicina, Universidad de Antioquia, Calle 62 #52-59, Torre 1, Laboratorio 610, Medellin 050001, Colombia"},{"name":"Escuela de Microbiolog\u00eda, Universidad de Antioquia, Calle 67 #53-108, Bloque 5, Oficina 5-135, Medellin 050001, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S1473-3099(07)70022-1","article-title":"Malaria in pregnancy: Pathogenesis and immunity","volume":"7","author":"Rogerson","year":"2007","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a025551","DOI":"10.1101\/cshperspect.a025551","article-title":"Malaria during Pregnancy","volume":"7","author":"Fried","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1086\/315135","article-title":"Malaria and pregnancy: Placental cytokine expression and its relationship to intrauterine growth retardation","volume":"180","author":"Moormann","year":"1999","journal-title":"J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Silver, K.L., Zhong, K., Leke, R.G.F., Taylor, D.W., and Kain, K.C. (2010). Dysregulation of angiopoietins is associated with placental malaria and low birth weight. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009481"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1093\/cid\/cix623","article-title":"Systemic inflammatory response to malaria during pregnancy is associated with pregnancy loss and preterm delivery","volume":"65","author":"Fried","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1086\/315449","article-title":"The impact of placental malaria on gestational age and birth weight","volume":"181","author":"Menendez","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.exppara.2005.12.003","article-title":"Plasmodium falciparum: Chondroitin sulfate A is the major receptor for adhesion of parasitized erythrocytes in the placenta","volume":"113","author":"Fried","year":"2006","journal-title":"Exp. Parasitol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.mam.2012.12.008","article-title":"Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia","volume":"34","author":"Ji","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_9","unstructured":"Wang, Y. (2010). Vascular Biology of the Placenta. Chapter 4: Cell Types of the Placenta, Morgan & Claypool Life Sciences."},{"key":"ref_10","first-page":"103","article-title":"Placental Villous Trophoblast: The Altered Balance between Proliferation and Apoptosis Triggers Pre-eclampsia","volume":"3","author":"Huppertz","year":"2006","journal-title":"J. Reprod. Med. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lawless, L., Qin, Y., Xie, L., and Zhang, K. (2023). Trophoblast Differentiation: Mechanisms and Implications for Pregnancy Complications. Nutrients, 15.","DOI":"10.3390\/nu15163564"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, R., Dang, Y.-L., Zheng, R., Li, Y., Li, W., Lu, X., Wang, L.-J., Zhu, C., Lin, H.-Y., and Wang, H. (2014). Live cell imaging of in vitro human trophoblast syncytialization. Biol. Reprod., 90.","DOI":"10.1095\/biolreprod.113.114892"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1093\/humupd\/dmab015","article-title":"Cell dynamics in human villous trophoblast","volume":"27","author":"Aplin","year":"2021","journal-title":"Hum. Reprod. Updat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.mce.2009.12.015","article-title":"New insights into the regulation of human cytotrophoblast cell differentiation","volume":"323","author":"Handwerger","year":"2010","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_15","first-page":"76","article-title":"Fusion of Cytothrophoblast with Syncytiotrophoblast in the Human Placenta: Factors Involved in Syncytialization","volume":"5","author":"Gauster","year":"2008","journal-title":"J. Reproduktionsmed. Endokrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1007\/s00018-019-03104-6","article-title":"Human placenta and trophoblast development: Key molecular mechanisms and model systems","volume":"76","author":"Haider","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/humrep\/dei272","article-title":"Differential effects of inducers of syncytialization and apoptosis on BeWo and JEG-3 choriocarcinoma cells","volume":"21","author":"Spitz","year":"2006","journal-title":"Hum. Reprod."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Liu, M., Hassana, S., and Stiles, J.K. (2016). Heme-mediated apoptosis and fusion damage in BeWo trophoblast cells. Sci. Rep., 6.","DOI":"10.1038\/srep36193"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/0014-4827(90)90310-7","article-title":"Modulators of cyclic AMP metabolism induce syncytiotrophoblast formation in vitro","volume":"186","author":"Wice","year":"1990","journal-title":"Exp. Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/273621a0","article-title":"Cultivation of malarial parasites","volume":"273","author":"Trager","year":"1978","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1186\/1475-2875-12-421","article-title":"Induction of pro-inflammatory response of the placental trophoblast by Plasmodium falciparum infected erythrocytes and TNF","volume":"12","author":"Segura","year":"2013","journal-title":"Malar. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/ncomms1551","article-title":"Identification of a link between Wnt\/\u03b2-catenin signalling and the cell fusion pathway","volume":"2","author":"Matsuura","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1128\/iai.65.4.1251-1257.1997","article-title":"Cytoadherence of Plasmodium falciparum to intercellular adhesion molecule 1 and chondroitin-4-sulfate expressed by the syncytiotrophoblast in the human placenta","volume":"65","author":"Maubert","year":"1997","journal-title":"Infect. Immun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1046\/j.1365-2958.2003.03570.x","article-title":"Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria","volume":"49","author":"Salanti","year":"2003","journal-title":"Mol. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.molbiopara.2006.03.006","article-title":"VAR2CSA is the principal ligand for chondroitin sulfate A in two allogeneic isolates of Plasmodium falciparum","volume":"148","author":"Duffy","year":"2006","journal-title":"Mol Biochem. Parasitol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1016\/S0002-9440(10)63761-3","article-title":"Plasmodium falciparum-infected erythrocytes adhere both in the intervillous space and on the villous surface of human placenta by binding to the low-sulfated chondroitin sulfate proteoglycan receptor","volume":"164","author":"Muthusamy","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1084\/jem.20041579","article-title":"Evidence for the involvement of VAR2CSA in pregnancy-associated malaria","volume":"200","author":"Salanti","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/S0143-4004(03)00173-5","article-title":"A two-colour fluorescence assay for the measurement of syncytial fusion between trophoblast-derived cell lines","volume":"24","author":"Borges","year":"2003","journal-title":"Placenta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12127","DOI":"10.1073\/pnas.0902925106","article-title":"Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene","volume":"106","author":"Dupressoir","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.placenta.2003.12.004","article-title":"Complex patterns of GCM1 mRNA and protein in villous and extravillous trophoblast cells of the human placenta","volume":"25","author":"Baczyk","year":"2004","journal-title":"Placenta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1139\/o05-026","article-title":"Biochemical characterization of the human placental transcription factor GCMa\/1","volume":"83","author":"Lin","year":"2005","journal-title":"Biochem. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/35001608","article-title":"Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis","volume":"403","author":"Mi","year":"2000","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1016\/j.celrep.2018.06.043","article-title":"Fine-Tuned and Cell-Cycle-Restricted Expression of Fusogenic Protein Syncytin-2 Maintains Functional Placental Syncytia","volume":"23","author":"Lu","year":"2018","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1530\/REP-10-0221","article-title":"The choriocarcinoma cell line BeWo: Syncytial fusion and expression of syncytium-specific proteins","volume":"140","author":"Orendi","year":"2010","journal-title":"Reproduction"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/path.2025","article-title":"Ultraviolet-inactivated human cytomegalovirus induces placental syncytiotrophoblast apoptosis in a Toll-like receptor-2 and tumour necrosis factor-alpha dependent manner","volume":"210","author":"Chan","year":"2006","journal-title":"J. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.placenta.2021.12.011","article-title":"Suppression of human trophoblast syncytialization by human cytomegalovirus infection","volume":"117","author":"Mimura","year":"2022","journal-title":"Placenta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1093\/infdis\/jiu019","article-title":"Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection","volume":"209","author":"Pereira","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1086\/377132","article-title":"Infection of placental trophoblasts by Toxoplasma gondii","volume":"188","author":"Abbasi","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101658","DOI":"10.1016\/j.tice.2021.101658","article-title":"BEWO trophoblast cells and Toxoplasma gondii infection modulate cell death mechanisms in THP-1 monocyte cells by interference in the expression of death receptor and intracellular proteins","volume":"73","author":"Angeloni","year":"2021","journal-title":"Tissue Cell."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.micpath.2016.08.022","article-title":"A local innate immune response against Trypanosoma cruzi in the human placenta: The epithelial turnover of the trophoblast","volume":"99","author":"Liempi","year":"2016","journal-title":"Microb. Pathog."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.placenta.2014.09.017","article-title":"Trypanosoma cruzi induces trophoblast differentiation: A potential local antiparasitic mechanism of the human placenta?","volume":"35","author":"Liempi","year":"2014","journal-title":"Placenta"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e210304","DOI":"10.1590\/0074-02760210304","article-title":"Chagas disease affects the human placental barrier\u2019s turnover dynamics during pregnancy","volume":"117","author":"Mezzano","year":"2022","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1038\/s41467-023-41158-0","article-title":"Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids","volume":"14","author":"Wu","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"102065","DOI":"10.1016\/j.parint.2020.102065","article-title":"Comparative ex vivo infection with Trypanosoma cruzi and Toxoplasma gondii of human, canine and ovine placenta: Analysis of tissue damage and infection efficiency","volume":"76","author":"Liempi","year":"2020","journal-title":"Parasitol. Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0928-8244(03)00279-7","article-title":"From cells to signaling cascades: Manipulation of innate immunity by Toxoplasma gondii","volume":"39","author":"Denkers","year":"2003","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41421-021-00324-8","article-title":"The molecular mechanism of cytoadherence to placental or tumor cells through VAR2CSA from Plasmodium falciparum","volume":"7","author":"Wang","year":"2021","journal-title":"Cell Discov."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ligasov\u00e1, A., and Koberna, K. (2021). Strengths and Weaknesses of Cell Synchronization Protocols Based on Inhibition of DNA Synthesis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910759"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Zhou, H., Zhao, C., Wang, P., Yang, W., Zhu, H., and Zhang, S. (2023). Regulators involved in trophoblast syncytialization in the placenta of intrauterine growth restriction. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1107182"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.micron.2005.12.011","article-title":"Trophoblast fusion: Fusogenic proteins, syncytins and ADAMs, and other prerequisites for syncytial fusion","volume":"37","author":"Huppertz","year":"2006","journal-title":"Micron"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/8\/1640\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:34:43Z","timestamp":1760110483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/12\/8\/1640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,10]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["microorganisms12081640"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms12081640","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,10]]}}}