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SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming.
Wu, Chien-Ting; Lidsky, Peter V; Xiao, Yinghong; Cheng, Ran; Lee, Ivan T; Nakayama, Tsuguhisa; Jiang, Sizun; He, Wei; Demeter, Janos; Knight, Miguel G; Turn, Rachel E; Rojas-Hernandez, Laura S; Ye, Chengjin; Chiem, Kevin; Shon, Judy; Martinez-Sobrido, Luis; Bertozzi, Carolyn R; Nolan, Garry P; Nayak, Jayakar V; Milla, Carlos; Andino, Raul; Jackson, Peter K.
  • Wu CT; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Center for Clinical Sciences Research, 269 Campus Drive, Stanford, CA, USA.
  • Lidsky PV; Department of Microbiology and Immunology, University of California, San Francisco, 600 16th Street, Room S572E, Box 2280, San Francisco, CA, USA.
  • Xiao Y; Department of Microbiology and Immunology, University of California, San Francisco, 600 16th Street, Room S572E, Box 2280, San Francisco, CA, USA.
  • Cheng R; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Center for Clinical Sciences Research, 269 Campus Drive, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA.
  • Lee IT; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Department of Otolaryngology-Head and Neck Surgery, Stanford University School o
  • Nakayama T; Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA; Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan.
  • Jiang S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • He W; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Center for Clinical Sciences Research, 269 Campus Drive, Stanford, CA, USA.
  • Demeter J; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Center for Clinical Sciences Research, 269 Campus Drive, Stanford, CA, USA.
  • Knight MG; Department of Microbiology and Immunology, University of California, San Francisco, 600 16th Street, Room S572E, Box 2280, San Francisco, CA, USA.
  • Turn RE; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Center for Clinical Sciences Research, 269 Campus Drive, Stanford, CA, USA.
  • Rojas-Hernandez LS; Department of Pediatric Pulmonary Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Ye C; Disease Intervention and Prevention and Population Health Programs, Texas Biomedical Research Institute, San Antonio, TX, USA.
  • Chiem K; Disease Intervention and Prevention and Population Health Programs, Texas Biomedical Research Institute, San Antonio, TX, USA.
  • Shon J; Department of Chemistry, Stanford University, Stanford, CA, USA.
  • Martinez-Sobrido L; Disease Intervention and Prevention and Population Health Programs, Texas Biomedical Research Institute, San Antonio, TX, USA.
  • Bertozzi CR; Department of Chemistry, Stanford University, Stanford, CA, USA.
  • Nolan GP; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Nayak JV; Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA; Department of Otolaryngology, VA Palo Alto Health Care System, Palo Alto, CA, USA.
  • Milla C; Department of Pediatric Pulmonary Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Andino R; Department of Microbiology and Immunology, University of California, San Francisco, 600 16th Street, Room S572E, Box 2280, San Francisco, CA, USA. Electronic address: raul.andino@ucsf.edu.
  • Jackson PK; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Center for Clinical Sciences Research, 269 Campus Drive, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: pjackson@stanfor
Cell ; 186(1): 112-130.e20, 2023 01 05.
Article in English | MEDLINE | ID: covidwho-2130296
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Respiratory System / SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Cell Year: 2023 Document Type: Article Affiliation country: J.cell.2022.11.030

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Respiratory System / SARS-CoV-2 / COVID-19 Topics: Variants Limits: Humans Language: English Journal: Cell Year: 2023 Document Type: Article Affiliation country: J.cell.2022.11.030