Dobrava-Belgrade virus (DOBV) is the main cause of hemorrhagic fever with renal syndrome (HFRS) in southern Europe. In its natural reservoirs, DOBV causes a persistent, asymptomatic infection and is spread through excretions, fighting, and grooming. Humans can become infected by inhaling aerosols that contain rodent saliva, urine, or feces, as well as through bites and scratches. In humans, infection causes fever and headache, as well as the appearance of spots on the skin and renal symptoms such as kidney swelling, excess protein in urine, blood in urine, decreased urine production, and kidney failure. Acute respiratory distress syndrome occurs in about 10% of cases. DOBV has four genotypes: Dobrava virus, Sochi virus, Kurkino virus, and Saaremaa virus. These genotypes are native to different rodent species and vary in how severe of illness they cause. Dobrava virus is carried by the yellow-necked mouse (Apodemus flavicollis) and has moderate-to-severe symptoms with a case fatality rate of 10–12%. Sochi virus is native to the Black Sea field mouse (Apodemus ponticus) and has moderate-to-severe symptoms and a case fatality rate of at least 6%. Kurkino virus is transmitted by the striped field mouse (Apodemus agrarius) and has mild-to-moderate symptoms with a 0.3–0.9% case fatality rate. Lastly, Saaremaa virus, also transmitted by the striped field mouse, is not associated with disease or mortality. The genome of DOBV is about 11.8 kilobases (kb) in length and segmented into three negative-sense, single-stranded RNA (-ssRNA) strands. The small strand encodes the viral nucleoprotein, the medium strand encodes the viral spike protein, which attaches to cell receptors for entry into cells, and the long strand encodes the viral RNA-dependent RNA polymerase (RdRp), which replicates and transcribes the genome. Genome segments are encased in nucleoproteins to form ribonucleoprotein (RNP) complexes that are surrounded by a viral envelope that contains spikes emanating from its surface. Dobrava-Belgrade virus replicates first by binding to the surface of cells with its envelope spikes. Virus particles, called virions, are then taken into the cell by endosomes, where a drop in pH causes the viral envelope to fuse with the endosome, which releases viral RNA into the host cell. RdRp then transcribes the genome for translation by host cell ribosomes and produces copies of the genome for progeny viruses. New virions are assembled at the endoplasmic reticulum and bud from its surface to obtain their viral envelope. Progeny viruses are then transported by a cellular vesicle to the cell membrane, where they leave the cell by exocytosis. Dobrava-Belgrade virus was first discovered in 1992 after being isolated from the lung tissue of a yellow-necked mouse in Dobrava, Slovenia. At the same time, an identical virus was identified in Belgrade, Serbia, earning the virus the name "Dobrava-Belgrade virus". Within a few years, the virus had been identified throughout Europe and Russia. The virus was implicated in an outbreak of HFRS in Croatia during the Balkan Wars. The main region affected by DOBV is southeastern Europe, but its distribution has been expanding since its hosts extend outside the region.
Genome The genome of Dobrava-Belgrade virus is about 11.8 thousand nucleotides in length and segmented into three negative-sense, single-stranded RNA (-ssRNA) strands. The segments form into circles via non-covalent bonding of the ends of the genome. The small segment, about 1.67 kilobases (kb) in length, encodes the viral nucleoprotein. The medium segment, about 3.64 kb in length. encodes a glycoprotein precursor that is cleaved into the two spike proteins Gn and Gc during virion assembly. The large segment, about 6.53 kb in length, encodes the viral RNA-dependent RNA polymerase (RdRp), which is responsible for transcribing and replicating the genome. The ends of each segment contain untranslated terminal regions (UTRs) that are involved in the replication and transcription of the genome.
Structure Virions are mostly spherical or pleomorphic in shape and range from 80 to 160 nm in diameter. They contain a lipid envelope covered in spike proteins made of the two viral glycoproteins, Gn and Gc. The spike proteins extend about 10 nm out from the surface and are tetrameric, consisting of four copies each of Gn and Gc with helical symmetry, in which Gn forms the stalk of the spike and Gc the head. Spikes are arranged on the surface in a lattice pattern. Inside the envelope are the three genome segments, which are encased in nucleoproteins to form a ribonucleoprotein (RNP) complex. Attached to each RNP complex is a copy of RdRp.
Life cycle DOBV primarily infects endothelial cells and macrophages. It enters cells by using β3-integrins as receptors. Virions are taken into a cell via an endosome. Once pH is lowered, the viral envelope fuses with the endosome, which releases viral RNA into the host cell's cytoplasm. The small segment is transcribed by RdRp first, then the medium segment, and lastly the large segment. Once the genome has been transcribed, RdRp snatches caps from host messenger RNA (mRNA) to create viral mRNA that is primed for translation by host ribosomes to produce viral proteins. For replication of the genome, a complementary positive-sense strand is produced by RdRp. Copies of the genome are made from this complementary strand. Progeny RNA strands are then encapsidated by nucleoproteins. During replication, the glycoprotein is cleaved in the endoplasmic reticulum by the host signal peptidase during translation. This produces Gn at the N-terminus and Gc at the C-terminus of the protein. Spike proteins are expressed on the surface of the endoplasmic reticulum. Viral RNPs are transported to the endoplasmic reticulum where they bud from the surface, thereby obtaining their envelope. Progeny viruses are then transported by a cellular vesicle to the cell membrane, where they leave the cell via exocytosis.
Diversity There are four genotypes of DOBV: Dobrava, Kurkino, Saaremaa, and Sochi. The Dobrava genotype causes infection mainly in southeastern Europe in Slovenia, Serbia, Montenegro, Albania, Greece, but also in central Europe in Czechia, Slovakia, and Hungary. The Kurkino genotype exists in Germany, Slovakia, Russia, Hungary, Slovenia, Croatia, and mainland Estonia. The Saaremaa genotype is found on Saaremaa island in Estonia. The Sochi genotype is found in the Black Sea region of eastern Russia.
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