Differential antiviral response of endothelial cells after infection with pathogenic and nonpathogenic hantaviruses.
Hantaviruses represent important human pathogens and can induce hemorrhagic fever with renal syndrome (HFRS), which is characterized by endothelial dysfunction. Both pathogenic and nonpathogenic hantaviruses replicate without causing any apparent cytopathic effect, suggesting that immunopathological mechanisms play an important role in pathogenesis. We compared the antiviral responses triggered by Hantaan virus (HTNV), a pathogenic hantavirus associated with HFRS, and Tula virus (TULV), a rather nonpathogenic hantavirus, in human umbilical vein endothelial cells (HUVECs). Both HTNV- and TULV-infected cells showed increased levels of molecules involved in antigen presentation. However, TULV-infected HUVECs upregulated HLA class I molecules more rapidly. Interestingly, HTNV clearly induced the production of beta interferon (IFN-beta), whereas expression of this cytokine was barely detectable in the supernatant or in extracts from TULV-infected HUVECs. Nevertheless, the upregulation of HLA class I on both TULV- and HTNV-infected cells could be blocked by neutralizing anti-IFN-beta antibodies. Most strikingly, the antiviral MxA protein, which interferes with hantavirus replication, was already induced 16 h after infection with TULV. In contrast, HTNV-infected HUVECs showed no expression of MxA until 48 h postinfection. In accordance with the kinetics of MxA expression, TULV replicated only inefficiently in HUVECs, whereas HTNV-infected cells produced high titers of virus particles that decreased after 48 h postinfection. Both hantavirus species, however, could replicate equally well in Vero E6 cells, which lack an IFN-induced MxA response. Thus, delayed induction of antiviral MxA in endothelial cells after infection with HTNV could allow viral dissemination and contribute to the pathogenesis leading to HFRS.
Kraus
Annette A
AA
Institut für Virologie, Charité-Universitätsmedizin Berlin, Schumannstrasse 20/21, D-10098 Berlin, Germany.
Raftery
Martin J
MJ
Giese
Thomas
T
Ulrich
Rainer
R
Zawatzky
Rainer
R
Hippenstiel
Stefan
S
Suttorp
Norbert
N
Krüger
Detlev H
DH
Schönrich
Günther
G
D000818:Animals; D002522:Chlorocebus aethiops; D042783:Endothelial Cells / Q000276:immunology* / Q000821:virology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D018063:Hantaan virus / Q000472:pathogenicity*; D006476:Orthohantavirus / Q000472:pathogenicity*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D014471:Umbilical Veins; D014709:Vero Cells; D014779:Virus Replication
D015395:Histocompatibility Antigens Class I; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D016899:Interferon-beta; D019204:GTP-Binding Proteins