SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity

Ramón Martínez-Mármol; Rosina Giordano-Santini; Eva Kaulich; Ann Na Cho; Magdalena Przybyla; Md Asrafuzzaman Riyadh; Emilija Robinson; Keng Yih Chew; Rumelo Amor; Frédéric A. Meunier; Giuseppe Balistreri; Kirsty R. Short; Yazi D. Ke; Lars M. Ittner; Massimo A. Hilliard

doi:10.1126/sciadv.adg2248

SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity

Ramón Martínez-Mármol, Rosina Giordano-Santini, Eva Kaulich, Ann Na Cho, Magdalena Przybyla, Md Asrafuzzaman Riyadh, Emilija Robinson, Keng Yih Chew, Rumelo Amor, Frédéric A. Meunier, Giuseppe Balistreri, Kirsty R. Short, Yazi D. Ke, Lars M. Ittner, Massimo A. Hilliard^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

49 Downloads (Pure)

Abstract

Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.

Original language	English
Article number	eadg2248
Pages (from-to)	1-14
Number of pages	14
Journal	Science Advances
Volume	9
Issue number	23
DOIs	https://doi.org/10.1126/sciadv.adg2248
Publication status	Published - 7 Jun 2023

Bibliographical note

Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Access to Document

10.1126/sciadv.adg2248Licence: CC BY

Publisher version (open access)Final published version, 1.94 MBLicence: CC BY

Cite this

Martínez-Mármol, R., Giordano-Santini, R., Kaulich, E., Cho, A. N., Przybyla, M., Riyadh, M. A., Robinson, E., Chew, K. Y., Amor, R., Meunier, F. A., Balistreri, G., Short, K. R., Ke, Y. D., Ittner, L. M., & Hilliard, M. A. (2023). SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity. Science Advances, 9(23), 1-14. Article eadg2248. https://doi.org/10.1126/sciadv.adg2248

@article{d4655974c96b47fd9ddae6f03dc38cb6,

title = "SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity",

abstract = "Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.",

author = "Ram{\'o}n Mart{\'i}nez-M{\'a}rmol and Rosina Giordano-Santini and Eva Kaulich and Cho, {Ann Na} and Magdalena Przybyla and Riyadh, {Md Asrafuzzaman} and Emilija Robinson and Chew, {Keng Yih} and Rumelo Amor and Meunier, {Fr{\'e}d{\'e}ric A.} and Giuseppe Balistreri and Short, {Kirsty R.} and Ke, {Yazi D.} and Ittner, {Lars M.} and Hilliard, {Massimo A.}",

note = "Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2023",

month = jun,

day = "7",

doi = "10.1126/sciadv.adg2248",

language = "English",

volume = "9",

pages = "1--14",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "23",

}

Martínez-Mármol, R, Giordano-Santini, R, Kaulich, E, Cho, AN, Przybyla, M, Riyadh, MA, Robinson, E, Chew, KY, Amor, R, Meunier, FA, Balistreri, G, Short, KR, Ke, YD , Ittner, LM & Hilliard, MA 2023, 'SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity', Science Advances, vol. 9, no. 23, eadg2248, pp. 1-14. https://doi.org/10.1126/sciadv.adg2248

TY - JOUR

T1 - SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity

AU - Martínez-Mármol, Ramón

AU - Giordano-Santini, Rosina

AU - Kaulich, Eva

AU - Cho, Ann Na

AU - Przybyla, Magdalena

AU - Riyadh, Md Asrafuzzaman

AU - Robinson, Emilija

AU - Chew, Keng Yih

AU - Amor, Rumelo

AU - Meunier, Frédéric A.

AU - Balistreri, Giuseppe

AU - Short, Kirsty R.

AU - Ke, Yazi D.

AU - Ittner, Lars M.

AU - Hilliard, Massimo A.

N1 - Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2023/6/7

Y1 - 2023/6/7

N2 - Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.

AB - Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.

UR - http://www.scopus.com/inward/record.url?scp=85161212311&partnerID=8YFLogxK

UR - https://purl.org/au-research/grants/nhmrc/GNT1123564

UR - https://purl.org/au-research/grants/nhmrc/GNT1136241

U2 - 10.1126/sciadv.adg2248

DO - 10.1126/sciadv.adg2248

M3 - Article

C2 - 37285437

AN - SCOPUS:85161212311

SN - 2375-2548

VL - 9

SP - 1

EP - 14

JO - Science Advances

JF - Science Advances

IS - 23

M1 - eadg2248

ER -

SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Novel pathomechanisms and treatment approaches in Alzheimer's disease and related forms of dementia

Novel pathomechanisms and therapeutic targets in neurodegenerative diseases

Cite this

SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Projects

Novel pathomechanisms and treatment approaches in Alzheimer's disease and related forms of dementia

Novel pathomechanisms and therapeutic targets in neurodegenerative diseases

Cite this