Fetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury

Introduction: Extracellular vesicles derived from the fetal central nervous system (FCNSEs) can be purified from maternal serum or plasma using the protein Contactin-2/TAG1that is expressed almost exclusively by developing neurons in the hippocampus, cerebral cortex and cerebellum. We hypothesized t...

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Autores principales:	Laura Goetzl, Angela J. Stephens, Yechiel Schlesinger, Nune Darbinian, Nana Merabova, Miriam Hillel, Alec J. Hirsch, Daniel N. Streblow, Antonio E. Frias, Victoria H. J. Roberts, Nicole N. Haese, Arunmani Mani, Yifat Eldar-Yedidia
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	exosomes/extracellular vesicles (EVs/ECVs) cytomegalovirus (CMV) Zika (ZIKV) Contactin-2 prenatal diagnosis microcephaly Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/311dd73ce289441aa9742497f6f4b333
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spelling	oai:doaj.org-article:311dd73ce289441aa9742497f6f4b3332021-11-19T04:35:30ZFetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury2673-818X10.3389/fviro.2021.782863https://doaj.org/article/311dd73ce289441aa9742497f6f4b3332021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fviro.2021.782863/fullhttps://doaj.org/toc/2673-818XIntroduction: Extracellular vesicles derived from the fetal central nervous system (FCNSEs) can be purified from maternal serum or plasma using the protein Contactin-2/TAG1that is expressed almost exclusively by developing neurons in the hippocampus, cerebral cortex and cerebellum. We hypothesized that fetal CNSEs could be used to non-invasively detect and quantify viral mediated in-utero brain injury in the first trimester.Materials and Methods: First trimester maternal samples were collected from a human clinical population infected with primary cytomegalovirus (CMV) and a non-human primate model of Zika (ZIKV) infection. In the CMV cohort, a nested case control study was performed comparing pregnancies with and without fetal infection. Cases of fetal infection were further subdivided into those with and without adverse neurologic outcome. ZIKV samples were collected serially following maternal inoculation or saline. All ZIKV cases had histopathologic findings on necropsy. Serum was precipitated with ExoQuick solution and FCEs were isolated with biotinylated anti-Contactin-2/TAG1 antibody-streptavidin matrix immunoabsorption. FCE Synaptopodin (SYNPO) and Neurogranin (NG) protein levels were measured using standard ELISA kits and normalized to the exosome marker CD81.Results: Fetal CNSE SYNPO and NG were significantly reduced in cases of first trimester fetal CMV infection compared to those with infection limited to the mother but could not discriminate between fetal infection with and without adverse neurologic outcome. Following ZIKV inoculation, fetal CNSE SYNPO was reduced by 48 h and significantly reduced by day 4.Discussion: These data are the first to suggest that first trimester non-invasive diagnosis of fetal viral infection is possible. Fetal CNSEs have the potential to augment clinical and pre-clinical studies of perinatal viral infection. Serial sampling may be needed to discriminate between fetuses that are responding to treatment and/or recovering due to innate defenses and those that have ongoing neuronal injury. If confirmed, this technology may advance the paradigm of first trimester prenatal diagnosis and change the calculus for the cost benefit of CMV surveillance programs in pregnancy.Laura GoetzlAngela J. StephensYechiel SchlesingerNune DarbinianNana MerabovaMiriam HillelAlec J. HirschAlec J. HirschDaniel N. StreblowDaniel N. StreblowAntonio E. FriasAntonio E. FriasVictoria H. J. RobertsNicole N. HaeseNicole N. HaeseArunmani ManiYifat Eldar-YedidiaFrontiers Media S.A.articleexosomes/extracellular vesicles (EVs/ECVs)cytomegalovirus (CMV)Zika (ZIKV)Contactin-2prenatal diagnosismicrocephalyMicrobiologyQR1-502ENFrontiers in Virology, Vol 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	exosomes/extracellular vesicles (EVs/ECVs) cytomegalovirus (CMV) Zika (ZIKV) Contactin-2 prenatal diagnosis microcephaly Microbiology QR1-502
spellingShingle	exosomes/extracellular vesicles (EVs/ECVs) cytomegalovirus (CMV) Zika (ZIKV) Contactin-2 prenatal diagnosis microcephaly Microbiology QR1-502 Laura Goetzl Angela J. Stephens Yechiel Schlesinger Nune Darbinian Nana Merabova Miriam Hillel Alec J. Hirsch Alec J. Hirsch Daniel N. Streblow Daniel N. Streblow Antonio E. Frias Antonio E. Frias Victoria H. J. Roberts Nicole N. Haese Nicole N. Haese Arunmani Mani Yifat Eldar-Yedidia Fetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury
description	Introduction: Extracellular vesicles derived from the fetal central nervous system (FCNSEs) can be purified from maternal serum or plasma using the protein Contactin-2/TAG1that is expressed almost exclusively by developing neurons in the hippocampus, cerebral cortex and cerebellum. We hypothesized that fetal CNSEs could be used to non-invasively detect and quantify viral mediated in-utero brain injury in the first trimester.Materials and Methods: First trimester maternal samples were collected from a human clinical population infected with primary cytomegalovirus (CMV) and a non-human primate model of Zika (ZIKV) infection. In the CMV cohort, a nested case control study was performed comparing pregnancies with and without fetal infection. Cases of fetal infection were further subdivided into those with and without adverse neurologic outcome. ZIKV samples were collected serially following maternal inoculation or saline. All ZIKV cases had histopathologic findings on necropsy. Serum was precipitated with ExoQuick solution and FCEs were isolated with biotinylated anti-Contactin-2/TAG1 antibody-streptavidin matrix immunoabsorption. FCE Synaptopodin (SYNPO) and Neurogranin (NG) protein levels were measured using standard ELISA kits and normalized to the exosome marker CD81.Results: Fetal CNSE SYNPO and NG were significantly reduced in cases of first trimester fetal CMV infection compared to those with infection limited to the mother but could not discriminate between fetal infection with and without adverse neurologic outcome. Following ZIKV inoculation, fetal CNSE SYNPO was reduced by 48 h and significantly reduced by day 4.Discussion: These data are the first to suggest that first trimester non-invasive diagnosis of fetal viral infection is possible. Fetal CNSEs have the potential to augment clinical and pre-clinical studies of perinatal viral infection. Serial sampling may be needed to discriminate between fetuses that are responding to treatment and/or recovering due to innate defenses and those that have ongoing neuronal injury. If confirmed, this technology may advance the paradigm of first trimester prenatal diagnosis and change the calculus for the cost benefit of CMV surveillance programs in pregnancy.
format	article
author	Laura Goetzl Angela J. Stephens Yechiel Schlesinger Nune Darbinian Nana Merabova Miriam Hillel Alec J. Hirsch Alec J. Hirsch Daniel N. Streblow Daniel N. Streblow Antonio E. Frias Antonio E. Frias Victoria H. J. Roberts Nicole N. Haese Nicole N. Haese Arunmani Mani Yifat Eldar-Yedidia
author_facet	Laura Goetzl Angela J. Stephens Yechiel Schlesinger Nune Darbinian Nana Merabova Miriam Hillel Alec J. Hirsch Alec J. Hirsch Daniel N. Streblow Daniel N. Streblow Antonio E. Frias Antonio E. Frias Victoria H. J. Roberts Nicole N. Haese Nicole N. Haese Arunmani Mani Yifat Eldar-Yedidia
author_sort	Laura Goetzl
title	Fetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury
title_short	Fetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury
title_full	Fetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury
title_fullStr	Fetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury
title_full_unstemmed	Fetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury
title_sort	fetal central nervous system derived extracellular vesicles: potential for non-invasive tracking of viral mediated fetal brain injury
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/311dd73ce289441aa9742497f6f4b333
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Fetal Central Nervous System Derived Extracellular Vesicles: Potential for Non-invasive Tracking of Viral Mediated Fetal Brain Injury

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