title: Influenza virus exploits tunneling nanotubes for cell-to-cell spread.
abstract: Tunneling nanotubes (TNTs) represent a novel route of intercellular communication. While previous work has shown that TNTs facilitate the exchange of viral or prion proteins from infected to naïve cells, it is not clear whether the viral genome is also transferred via this mechanism and further, whether transfer via this route can result in productive replication of the infectious agents in the recipient cell. Here we present evidence that lung epithelial cells are connected by TNTs, and in spite of the presence of neutralizing antibodies and an antiviral agent, Oseltamivir, influenza virus can exploit these networks to transfer viral proteins and genome from the infected to naïve cell, resulting in productive viral replication in the naïve cells. These observations indicate that influenza viruses can spread using these intercellular networks that connect epithelial cells, evading immune and antiviral defenses and provide an explanation for the incidence of influenza infections even in influenza-immune individuals and vaccine failures.
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Jin Hyang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Ranjan
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Maureen G
authors.initials: MG
authors.lastname: Metcalfe
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Cao
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Mishina
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Shivaprakash
authors.initials: S
authors.lastname: Gangappa
authors.affiliation: Virus Surveillance and Diagnostics Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Media Lab, McGovern Institute, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Boyden
authors.affiliation: Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Sherif
authors.initials: S
authors.lastname: Zaki
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: York
authors.affiliation: Department of Microbiology, Department of Infectious Disease, Global Health and Emerging Pathogens Institute and Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Office of Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shaw
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.
authors.forename: Suryaprakash
authors.initials: S
authors.lastname: Sambhara
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000648:ultrastructure; D016679:Genome, Viral; D006801:Humans; D008168:Lung / Q000166:cytology; D009068:Movement; D043942:Nanotubes / Q000737:chemistry* / Q000648:ultrastructure; D009975:Orthomyxoviridae / Q000235:genetics / Q000502:physiology*; D058105:Polymerization; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D014764:Viral Proteins