Puumala virus (PUUV) is the main cause of hemorrhagic fever with renal syndrome (HFRS) in Europe and Russia. Puumala virus is transmitted by the bank vole (Clethrionomys glareolus). In its natural reservoir, PUUV causes a persistent infection with few symptoms 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 is usually asymptomatic but can lead to a mild form of HFRS often called nephropathia epidemica (NE). Symptoms include fever and headache, impaired vision, 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. The case fatality rate from infection is less than 1%. The genome of PUUV is about 12 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 a non-structural protein that interferes with interferon production, 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. Puumala 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. PUUV was discovered in 1980 after being extracted from bank voles. The virus was subsequently linked to a past outbreak among soldiers in Finland during World War Two, when the disease received the name nephropathia epidemica. A similar outbreak occurred among soldiers in Croatia during the Balkan Wars. PUUV is found throughout Europe and Russia where the vole bank lives. Finland is the country most affected by PUUV and experiences thousands of infections each year. While infection is typically associated with HFRS, Puumala virus can cause hantavirus pulmonary syndrome on rare occasions.
Genome
The genome of Puumala virus is about 12 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 1.83 kilobases (kb) in length, encodes the viral nucleoprotein and a non-structural protein that inhibits interferon production. The medium segment, about 3.65 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 6.55 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
PUUV 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.
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