Molecular Diagnostics of Hemorrhagic Fever with Renal Syndrome during a Dobrava Virus Infection Outbreak in the European Part of Russia

Abstract

A large outbreak of hemorrhagic fever with renal syndrome (HFRS) occurred in the winter of 2006-2007 in a region southeast of Moscow in Central European Russia. Of the 422 patients with HFRS investigated in this study, 58 patients were found to be infected by Puumala virus, whereas as many as 364 were infected by Dobrava-Belgrade virus (DOBV). Early serum samples from 10 DOBV-infected patients were used for nucleic acid amplification, which was successful for 5 patients. Molecular analyses demonstrated that the causative hantavirus belongs to the DOBV-Aa genetic lineage, which is carried by the striped field mouse (Apodemus agrarius) as the natural reservoir host. Neutralization assays with convalescent-phase sera from these patients confirmed infection by DOBV-Aa; related viruses, such as the Dobrava-Slovenia virus (DOBV-Af) and the Dobrava-Sochi virus (DOBV-Ap), were neutralized at lower efficiencies. The clinical courses of the 205 patients enrolled in the study were found to be mostly mild to moderate; however, an unexpectedly high fraction (27%) of patients exhibited severe illness. One patient died from kidney failure and showed symptoms of generalized subcutaneous hemorrhage. The results provide molecular, serodiagnostic, and clinical evidence that DOBV-Aa is a common pathogen in East Europe that causes large outbreaks of HFRS.Hemorrhagic fever with renal syndrome (HFRS) is an infectious disease caused by hantaviruses in Asia and Europe (16,20) and most probably in Africa (13; our unpublished results). In the Americas, the autochthonous hantavirus species cause the hantavirus (cardio)pulmonary syndrome (24,26). Hantaviruses carry trisegmented negative-strand RNA genomes and belong to the family Bunyaviridae. Different rodent species are known to be the natural hosts of the currently identified hantaviruses pathogenic for humans (16,20). The viruses are transmitted to humans by aerosolized rodent excreta. Shrews were shown to be alternative hantavirus hosts (14, 31); however, the clinical significance of shrew-borne hantaviruses is still unclear.The demonstration of viral nucleotide sequences in specimens derived from patients with HFRS gives a clue to the involvement of a particular virus in the infection and allows its detailed molecular phylogenetic characterization. Because of the short-term viremia typical for human hantavirus infections, viral genetic material can best be amplified from blood or plasma during the first days after the onset of clinical symptoms (16). In contrast, serotyping of neutralizing antibodies is suggested to be most significant when convalescent-phase sera from the patients are used (19).HFRS cases in the European administrative regions of Russia are contributing to 97% of the total number of HFRS cases registered in Russia. Until recently, the majority of HFRS cases in European Russia were caused by Puumala virus (PUUV) and considerably fewer (mainly sporadic cases) were caused by Dobrava-Belgrade virus (DOBV) infections. However, during the period from 1991 to 2006, three l...

Genetic reassortment between high-virulent and low-virulent Dobrava-Belgrade virus strains

“…It is important to note that infection by DOBV-Af in South-East Europe causes a higher percentage of severe and lethal clinical cases than has been observed for infections by DOBV-Aa in Central and East Europe (for a compilation of data see [33] and [44]). For other hantaviruses, it was previously shown that different virulence in humans is paralleled in vitro by differential induction of innate immune responses in host cells [40,[45][46][47][48][49]; for a review see [21].…”

“…Based on molecular diagnostics and serotyping of patients' specimens as well as clinical studies, it has been found that DOBV-Af generates moderate to severe HFRS with case fatality rates of 10% [29,30], whereas DOBV-Aa infections lead to mild to moderate HFRS with 0.6-0.9% case fatalities [26,[31][32][33]. This shows that highly related viruses of the DOBV complex exhibit different degrees of virulence in humans.…”

The broad spectrum of hantaviruses and their hosts in Central Europe

“…Infections by DOBV-Dobrava in the Balkans cause moderate to severe disease with case fatality rates of 10-12%, whereas our investigations of large HFRS outbreaks in Russia due to DOBV-Kurkino infections showed mild to moderate courses with 0.3-0.9% case fatality (Dzagurova et al, 2009;Klempa et al, 2013a;Papa, 2012).…”

Hantavirus protein interactions regulate cellular functions and signaling responses

“…In certain areas of Europe, several different hantaviruses are circulating and it is therefore not always possible to know which specific hantavirus a patient has been infected with unless specific serotyping or neutralization tests are performed [56][57][58]. Hence the observed clinical picture of HFRS patients reported from these areas could actually be a mixture of DOBV, PUUV and perhaps even SEOV infection.…”