title: Nanoparticle exposure reactivates latent herpesvirus and restores a signature of acute infection.
abstract: Inhalation of environmental (nano) particles (NP) as well as persistent herpesvirus-infection are potentially associated with chronic lung disease and as both are omnipresent in human society a coincidence of these two factors is highly likely. We hypothesized that NP-exposure of persistently herpesvirus-infected cells as a second hit might disrupt immune control of viral latency, provoke reactivation of latent virus and eventually lead to an inflammatory response and tissue damage.
  
  
  
  To test this hypothesis, we applied different NP to cells or mice latently infected with murine gammaherpesvirus 68 (MHV-68) which provides a small animal model for the study of gammaherpesvirus-pathogenesis in vitro and in vivo. In vitro, NP-exposure induced expression of the typically lytic viral gene ORF50 and production of lytic virus. In vivo, lytic viral proteins in the lung increased after intratracheal instillation with NP and elevated expression of the viral gene ORF50 could be detected in cells from bronchoalveolar lavage. Gene expression and metabolome analysis of whole lung tissue revealed patterns with striking similarities to acute infection. Likewise, NP-exposure of human cells latently infected with Epstein-Barr-Virus also induced virus production.
  
  
  
  Our results indicate that NP-exposure of persistently herpesvirus-infected cells - murine or human - restores molecular signatures found in acute virus infection, boosts production of lytic viral proteins, and induces an inflammatory response in the lung - a combination which might finally result in tissue damage and pathological alterations.
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Sattler
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Research Unit BioGeoChemistry, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.
authors.forename: Franco
authors.initials: F
authors.lastname: Moritz
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.
authors.forename: Shanze
authors.initials: S
authors.lastname: Chen
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Marchioninistrasse 25, D-81377, Munich, Germany.|University Hospital Grosshadern, Ludwig-Maximilians-University, D-81377, Munich, Germany.|Comprehensive Pneumology Center, Member of the German Center of Lung Research (DZL), D-81377, Munich, Germany.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Steer
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Kutschke
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Institute of Experimental Genetics, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Institute of Experimental Genetics, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.|Technische Universität München, Chair of Experimental Genetics, D-85354, Freising, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Research Unit BioGeoChemistry, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.
authors.forename: Philippe
authors.initials: P
authors.lastname: Schmitt-Kopplin
authors.affiliation: Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Marchioninistrasse 25, D-81377, Munich, Germany. h.adler@helmholtz-muenchen.de.|University Hospital Grosshadern, Ludwig-Maximilians-University, D-81377, Munich, Germany. h.adler@helmholtz-muenchen.de.|Comprehensive Pneumology Center, Member of the German Center of Lung Research (DZL), D-81377, Munich, Germany. h.adler@helmholtz-muenchen.de.
authors.forename: Heiko
authors.initials: H
authors.lastname: Adler
authors.affiliation: Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany. tobias.stoeger@helmholtz-muenchen.de.
authors.forename: Tobias
authors.identifier: 0000-0002-2790-0389
authors.initials: T
authors.lastname: Stoeger
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D018142:Gammaherpesvirinae / Q000187:drug effects* / Q000502:physiology; D006566:Herpesviridae Infections / Q000821:virology*; D051379:Mice; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000633:toxicity*; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency; D014779:Virus Replication
keywords: Carbonaceous nanoparticles (CNP); Double-walled carbon nanotubes (DWCNT); Intratracheal instillation; Persistent virus infection; Phospholipids; Virus reactivation