TMEFF1 is a neuron-specific restriction factor for herpes simplex virus

Yao Dai; Manja Idorn; Manutea C. Serrero; Xiaoyong Pan; Emil A. Thomsen; Ryo Narita; Muyesier Maimaitili; Xiaoqing Qian; Marie B. Iversen; Line S. Reinert; Rasmus K. Flygaard; Muwan Chen; Xiangning Ding; Bao Cun Zhang; Madalina E. Carter-Timofte; Qing Lu; Zhuofan Jiang; Yiye Zhong; Shuhui Zhang; Lintai Da; Jinwei Zhu; Mark Denham; Poul Nissen; Trine H. Mogensen; Jacob Giehm Mikkelsen; Shen Ying Zhang; Jean Laurent Casanova; Yujia Cai; Søren R. Paludan

doi:10.1038/s41586-024-07670-z

TMEFF1 is a neuron-specific restriction factor for herpes simplex virus

Yao Dai, Manja Idorn, Manutea C. Serrero, Xiaoyong Pan, Emil A. Thomsen, Ryo Narita, Muyesier Maimaitili, Xiaoqing Qian, Marie B. Iversen, Line S. Reinert, Rasmus K. Flygaard, Muwan Chen, Xiangning Ding, Bao Cun Zhang, Madalina E. Carter-Timofte, Qing Lu, Zhuofan Jiang, Yiye Zhong, Shuhui Zhang, Lintai DaJinwei Zhu, Mark Denham, Poul Nissen, Trine H. Mogensen, Jacob Giehm Mikkelsen, Shen Ying Zhang, Jean Laurent Casanova, Yujia Cai^*, Søren R. Paludan^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

The brain is highly sensitive to damage caused by infection and inflammation^1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis³. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus–cell binding and virus–cell fusion, respectively^4–6. Notably, Tmeff1^−/− mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.

Original language	English
Journal	Nature
Volume	632
Issue	8024
Pages (from-to)	383-389
Number of pages	7
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-024-07670-z
Publication status	Published - Aug 2024

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Dai, Y., Idorn, M., Serrero, M. C., Pan, X., Thomsen, E. A., Narita, R., Maimaitili, M., Qian, X., Iversen, M. B., Reinert, L. S., Flygaard, R. K., Chen, M., Ding, X., Zhang, B. C., Carter-Timofte, M. E., Lu, Q., Jiang, Z., Zhong, Y., Zhang, S., ... Paludan, S. R. (2024). TMEFF1 is a neuron-specific restriction factor for herpes simplex virus. Nature, 632(8024), 383-389. https://doi.org/10.1038/s41586-024-07670-z

@article{37696816787c4d8e836c5447b020c42e,

title = "TMEFF1 is a neuron-specific restriction factor for herpes simplex virus",

abstract = "The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus–cell binding and virus–cell fusion, respectively4–6. Notably, Tmeff1−/− mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.",

author = "Yao Dai and Manja Idorn and Serrero, {Manutea C.} and Xiaoyong Pan and Thomsen, {Emil A.} and Ryo Narita and Muyesier Maimaitili and Xiaoqing Qian and Iversen, {Marie B.} and Reinert, {Line S.} and Flygaard, {Rasmus K.} and Muwan Chen and Xiangning Ding and Zhang, {Bao Cun} and Carter-Timofte, {Madalina E.} and Qing Lu and Zhuofan Jiang and Yiye Zhong and Shuhui Zhang and Lintai Da and Jinwei Zhu and Mark Denham and Poul Nissen and Mogensen, {Trine H.} and Mikkelsen, {Jacob Giehm} and Zhang, {Shen Ying} and Casanova, {Jean Laurent} and Yujia Cai and Paludan, {S{\o}ren R.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.",

year = "2024",

month = aug,

doi = "10.1038/s41586-024-07670-z",

language = "English",

volume = "632",

pages = "383--389",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "8024",

}

Dai, Y, Idorn, M , Serrero, MC, Pan, X, Thomsen, EA , Narita, R , Maimaitili, M, Qian, X, Iversen, MB , Reinert, LS , Flygaard, RK , Chen, M , Ding, X, Zhang, BC, Carter-Timofte, ME, Lu, Q, Jiang, Z, Zhong, Y, Zhang, S, Da, L, Zhu, J, Denham, M , Nissen, P , Mogensen, TH , Mikkelsen, JG, Zhang, SY, Casanova, JL, Cai, Y & Paludan, SR 2024, 'TMEFF1 is a neuron-specific restriction factor for herpes simplex virus', Nature, vol. 632, no. 8024, pp. 383-389. https://doi.org/10.1038/s41586-024-07670-z

TY - JOUR

T1 - TMEFF1 is a neuron-specific restriction factor for herpes simplex virus

AU - Dai, Yao

AU - Idorn, Manja

AU - Serrero, Manutea C.

AU - Pan, Xiaoyong

AU - Thomsen, Emil A.

AU - Narita, Ryo

AU - Maimaitili, Muyesier

AU - Qian, Xiaoqing

AU - Iversen, Marie B.

AU - Reinert, Line S.

AU - Flygaard, Rasmus K.

AU - Chen, Muwan

AU - Ding, Xiangning

AU - Zhang, Bao Cun

AU - Carter-Timofte, Madalina E.

AU - Lu, Qing

AU - Jiang, Zhuofan

AU - Zhong, Yiye

AU - Zhang, Shuhui

AU - Da, Lintai

AU - Zhu, Jinwei

AU - Denham, Mark

AU - Nissen, Poul

AU - Mogensen, Trine H.

AU - Mikkelsen, Jacob Giehm

AU - Zhang, Shen Ying

AU - Casanova, Jean Laurent

AU - Cai, Yujia

AU - Paludan, Søren R.

PY - 2024/8

Y1 - 2024/8

N2 - The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus–cell binding and virus–cell fusion, respectively4–6. Notably, Tmeff1−/− mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.

AB - The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus–cell binding and virus–cell fusion, respectively4–6. Notably, Tmeff1−/− mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.

UR - http://www.scopus.com/inward/record.url?scp=85199317638&partnerID=8YFLogxK

U2 - 10.1038/s41586-024-07670-z

DO - 10.1038/s41586-024-07670-z

M3 - Journal article

C2 - 39048823

AN - SCOPUS:85199317638

SN - 0028-0836

VL - 632

SP - 383

EP - 389

JO - Nature

JF - Nature

IS - 8024

ER -

TMEFF1 is a neuron-specific restriction factor for herpes simplex virus

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