SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming

Chien-Ting Wu; Peter V. Lidsky; Yinghong Xiao; Ran Cheng; Ivan T. Lee; Tsuguhisa Nakayama; Sizun Jiang; Wei He; Janos Demeter; Miguel G. Knight; Rachel E. Turn; Laura S. Rojas-Hernandez; Chengjin Ye; Kevin Chiem; Judy Shon; Luis Martinez-Sobrido; Carolyn R. Bertozzi; Garry P. Nolan; Jayakar V. Nayak; Carlos Milla; Raul Andino; Peter K. Jackson

doi:10.1016/j.cell.2022.11.030

SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming

Chien-Ting Wu, Peter V. Lidsky, Yinghong Xiao, Ran Cheng, Ivan T. Lee, Tsuguhisa Nakayama, Sizun Jiang, Wei He, Janos Demeter, Miguel G. Knight, Rachel E. Turn, Laura S. Rojas-Hernandez, Chengjin Ye, Kevin Chiem, Judy Shon, Luis Martinez-Sobrido, Carolyn R. Bertozzi, Garry P. Nolan, Jayakar V. Nayak, Carlos MillaRaul Andino^*, Peter K. Jackson^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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Abstract

How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia. © 2022 The Authors

Original language	English
Pages (from-to)	112-130.e20
Journal	Cell
Volume	186
Issue number	1
Online published	2 Dec 2022
DOIs	https://doi.org/10.1016/j.cell.2022.11.030
Publication status	Published - 5 Jan 2023
Externally published	Yes

Research Keywords

airway epithelial cells
cilia
COVID-19
microvilli
organoids
protein kinases
proteomics
respiratory synctital virus
respiratory virus
SARS-CoV-2

Publisher's Copyright Statement

This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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231907125.pdfFinal Published version, 19.8 MBLicence: CC BY-NC-ND

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Wu, C.-T., Lidsky, P. V., Xiao, Y., Cheng, R., Lee, I. T., Nakayama, T., Jiang, S., He, W., Demeter, J., Knight, M. G., Turn, R. E., Rojas-Hernandez, L. S., Ye, C., Chiem, K., Shon, J., Martinez-Sobrido, L., Bertozzi, C. R., Nolan, G. P., Nayak, J. V., ... Jackson, P. K. (2023). SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming. Cell, 186(1), 112-130.e20. https://doi.org/10.1016/j.cell.2022.11.030

@article{360ff9440fe54653819d9aab6b1c9222,

title = "SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming",

abstract = "How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia. {\textcopyright} 2022 The Authors",

keywords = "airway epithelial cells, cilia, COVID-19, microvilli, organoids, protein kinases, proteomics, respiratory synctital virus, respiratory virus, SARS-CoV-2",

author = "Chien-Ting Wu and Lidsky, {Peter V.} and Yinghong Xiao and Ran Cheng and Lee, {Ivan T.} and Tsuguhisa Nakayama and Sizun Jiang and Wei He and Janos Demeter and Knight, {Miguel G.} and Turn, {Rachel E.} and Rojas-Hernandez, {Laura S.} and Chengjin Ye and Kevin Chiem and Judy Shon and Luis Martinez-Sobrido and Bertozzi, {Carolyn R.} and Nolan, {Garry P.} and Nayak, {Jayakar V.} and Carlos Milla and Raul Andino and Jackson, {Peter K.}",

year = "2023",

month = jan,

day = "5",

doi = "10.1016/j.cell.2022.11.030",

language = "English",

volume = "186",

pages = "112--130.e20",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "1",

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Wu, C-T, Lidsky, PV, Xiao, Y, Cheng, R, Lee, IT, Nakayama, T, Jiang, S, He, W, Demeter, J, Knight, MG, Turn, RE, Rojas-Hernandez, LS, Ye, C, Chiem, K, Shon, J, Martinez-Sobrido, L, Bertozzi, CR, Nolan, GP, Nayak, JV, Milla, C, Andino, R & Jackson, PK 2023, 'SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming', Cell, vol. 186, no. 1, pp. 112-130.e20. https://doi.org/10.1016/j.cell.2022.11.030

TY - JOUR

T1 - SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming

AU - Wu, Chien-Ting

AU - Lidsky, Peter V.

AU - Xiao, Yinghong

AU - Cheng, Ran

AU - Lee, Ivan T.

AU - Nakayama, Tsuguhisa

AU - Jiang, Sizun

AU - He, Wei

AU - Demeter, Janos

AU - Knight, Miguel G.

AU - Turn, Rachel E.

AU - Rojas-Hernandez, Laura S.

AU - Ye, Chengjin

AU - Chiem, Kevin

AU - Shon, Judy

AU - Martinez-Sobrido, Luis

AU - Bertozzi, Carolyn R.

AU - Nolan, Garry P.

AU - Nayak, Jayakar V.

AU - Milla, Carlos

AU - Andino, Raul

AU - Jackson, Peter K.

PY - 2023/1/5

Y1 - 2023/1/5

N2 - How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia. © 2022 The Authors

AB - How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia. © 2022 The Authors

KW - airway epithelial cells

KW - cilia

KW - COVID-19

KW - microvilli

KW - organoids

KW - protein kinases

KW - proteomics

KW - respiratory synctital virus

KW - respiratory virus

KW - SARS-CoV-2

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UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85143897146&origin=recordpage

U2 - 10.1016/j.cell.2022.11.030

DO - 10.1016/j.cell.2022.11.030

M3 - RGC 21 - Publication in refereed journal

C2 - 36580912

SN - 0092-8674

VL - 186

SP - 112-130.e20

JO - Cell

JF - Cell

IS - 1

ER -

SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming

Abstract

Research Keywords

Publisher's Copyright Statement

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