Reovirus infection is regulated by NPC1 and endosomal cholesterol homeostasis.

Autor: Ortega-Gonzalez P; Cell Structure Laboratory, National Center for Biotechnology, CNB-CSIC, campus UAM, Cantoblanco, Madrid, Spain.; PhD Program in Molecular Biosciences, Autonoma de Madrid University, Madrid, Spain.; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., Taylor G; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., Jangra RK; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America., Tenorio R; Cell Structure Laboratory, National Center for Biotechnology, CNB-CSIC, campus UAM, Cantoblanco, Madrid, Spain., Fernandez de Castro I; Cell Structure Laboratory, National Center for Biotechnology, CNB-CSIC, campus UAM, Cantoblanco, Madrid, Spain., Mainou BA; Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America., Orchard RC; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America., Wilen CB; Departments of Laboratory Medicine and Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America., Brigleb PH; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America., Sojati J; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America., Chandran K; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America., Sachse M; Cell Structure Laboratory, National Center for Biotechnology, CNB-CSIC, campus UAM, Cantoblanco, Madrid, Spain., Risco C; Cell Structure Laboratory, National Center for Biotechnology, CNB-CSIC, campus UAM, Cantoblanco, Madrid, Spain., Dermody TS; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2022 Mar 09; Vol. 18 (3), pp. e1010322. Date of Electronic Publication: 2022 Mar 09 (Print Publication: 2022).
DOI: 10.1371/journal.ppat.1010322
Abstrakt: Cholesterol homeostasis is required for the replication of many viruses, including Ebola virus, hepatitis C virus, and human immunodeficiency virus-1. Niemann-Pick C1 (NPC1) is an endosomal-lysosomal membrane protein involved in cholesterol trafficking from late endosomes and lysosomes to the endoplasmic reticulum. We identified NPC1 in CRISPR and RNA interference screens as a putative host factor for infection by mammalian orthoreovirus (reovirus). Following internalization via clathrin-mediated endocytosis, the reovirus outer capsid is proteolytically removed, the endosomal membrane is disrupted, and the viral core is released into the cytoplasm where viral transcription, genome replication, and assembly take place. We found that reovirus infection is significantly impaired in cells lacking NPC1, but infection is restored by treatment of cells with hydroxypropyl-β-cyclodextrin, which binds and solubilizes cholesterol. Absence of NPC1 did not dampen infection by infectious subvirion particles, which are reovirus disassembly intermediates that bypass the endocytic pathway for infection of target cells. NPC1 is not required for reovirus attachment to the plasma membrane, internalization into cells, or uncoating within endosomes. Instead, NPC1 is required for delivery of transcriptionally active reovirus core particles from endosomes into the cytoplasm. These findings suggest that cholesterol homeostasis, ensured by NPC1 transport activity, is required for reovirus penetration into the cytoplasm, pointing to a new function for NPC1 and cholesterol homeostasis in viral infection.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: K.C. is a member of the scientific advisory boards of Integrum Scientific, LLC, Biovaxys Technology Corp, and the Pandemic Security Initiative of Celdara Medical, LLC.
Databáze: MEDLINE
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