Dobrava-Belgrade Hantavirus from Germany Shows Receptor Usage and Innate Immunity Induction Consistent with the Pathogenicity of the Virus in Humans

Elena Popugaeva,Boris Klempa,Mathias Schlegel,Rainer G Ulrich,Andreas Rang,Brita Auste,Peter T Witkowski,Detlev H Krüger,Volker Thiel

doi:10.1371/journal.pone.0035587

Abstract

BackgroundDobrava-Belgrade virus (DOBV) is a European hantavirus causing hemorrhagic fever with renal syndrome (HFRS) in humans with fatality rates of up to 12%. DOBV-associated clinical cases typically occur also in the northern part of Germany where the virus is carried by the striped field mouse (Apodemus agrarius). However, the causative agent responsible for human illness has not been previously isolated.Methodology/Principal FindingsHere we report on characterization of a novel cell culture isolate from Germany obtained from a lung tissue of “spillover” infected yellow necked mouse (A. flavicollis) trapped near the city of Greifswald. Phylogenetic analyses demonstrated close clustering of the new strain, designated Greifswald/Aa (GRW/Aa) with the nucleotide sequence obtained from a northern German HFRS patient. The virus was effectively blocked by specific antibodies directed against β3 integrins and Decay Accelerating Factor (DAF) indicating that the virus uses same receptors as the highly pathogenic Hantaan virus (HTNV). In addition, activation of selected innate immunity markers as interferon β and λ and antiviral protein MxA after viral infection of A549 cells was investigated and showed that the virus modulates the first-line antiviral response in a similar way as HTNV.Conclusions/SignificanceIn summary, our study reveals novel data on DOBV receptor usage and innate immunity induction in relationship to virus pathogenicity and underlines the potency of German DOBV strains to act as human pathogen.

Highlights

Hantaviruses (Bunyaviridae family) are rodent-borne emerging viruses which cause two significant human diseases; hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe, and hantavirus cardiopulmonary syndrome in the Americas
Dobrava-Belgrade virus (DOBV)-IgG ELISA and RT-PCR revealed altogether 11 A. agrarius and A. flavicollis animals infected with viruses of the DOBV-Aa lineage [10]
After six weeks of blind passaging DOBV infected cells were detected by immunofluorescence assay only for the GER/08/131/A. flavicollis (Af) sample and the presence of viral RNA in the corresponding cell culture supernatant was confirmed by RT-PCR

Summary

Introduction

Hantaviruses (Bunyaviridae family) are rodent-borne emerging viruses which cause two significant human diseases; hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe, and hantavirus cardiopulmonary syndrome in the Americas. They carry a segmented, single-stranded RNA genome of negative polarity. Moderate to severe HFRS cases in South European Russia have been associated with DOBV-Ap lineage, represented by Sochi/Ap strain, transmitted by A. ponticus (Ap) [6]. Dobrava-Belgrade virus (DOBV) is a European hantavirus causing hemorrhagic fever with renal syndrome (HFRS) in humans with fatality rates of up to 12%. The causative agent responsible for human illness has not been previously isolated

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