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Aura R. Garrison, Sergey V. Alkhovsky [Альховский Сергей Владимирович], Tatjana Avšič-Županc, Dennis A. Bente, Éric Bergeron, Felicity Burt, Nicholas Di Paola, Koray Ergünay, Roger Hewson, Jens H. Kuhn, Ali Mirazimi, Anna Papa [Άννα Παπά], Amadou Alpha Sall, Jessica R. Spengler, and Gustavo Palacios
Corresponding author: Gustavo Palacios (email@example.com) Edited by: Jens H. Kuhn and Stuart G. Siddell Posted: July 2020
Members of the family Nairoviridae produce enveloped virions containing genomes consisting of three negative-sense, single-stranded RNA segments totalling 17.1–22.8 kb (S: 1.7–2.1 kb; M: 4.4–6.3 kb; L: 11.2–14.4 kb) (Table 1.Nairoviridae). Nairoviruses are classified into three genera (Orthonairovirus, Shaspivirus, and Striwavirus). These viruses are maintained in arthropods or transmitted by ticks among mammals, birds, or bats. The most important nairovirus with public-health impact is Crimean-Congo hemorrhagic fever virus, which is tick-borne and endemic in much of Asia, Africa, Southern and Eastern Europe. The most significant nairovirus with veterinary importance is Nairobi sheep disease virus, which is also tick-borne and causes lethal hemorrhagic gastroenteritis in small ruminants in Africa and India.
Table 1.Nairoviridae. Characteristics of members of the family Nairoviridae
Dugbe virus [S segment: AF434161; M segment: M94133; L segment: U15018], species Dugbe orthonairovirus, genus Orthonairovirus
Enveloped, spherical virions 80–120 nm in diameter with heterodimer surface spikes
Three single-stranded, negative-sense RNA molecules, S, M, and L of about 2 kb, about 5 kb, and about 12 kb, respectively
Cytoplasmic. The nucleocapsid protein (N) encapsidates the genomic RNA forming ribonucleoprotein (RNP) complexes with the viral RNA-directed RNA polymerase (RdRP)-containing large protein (L). Anti-genomic RNAs are generated and serve as templates for synthesis of nascent RNP complexes containing genomic RNA
From capped mRNAs that lack poly(A) termini. The 5′-cap structure is derived from cellular mRNAs via cap-snatching
Birds, humans, rodents, hares, shrews, ruminants, bats, ticks (Orthonairovirus); spider vector (Shaspivirus) or water strider vector (Striwavirus) with unknown host range
Realm Riboviria, kingdom Orthornavirae, phylum Negarnaviricota, subphylum Polyploviricotina, class Ellioviricetes, order Bunyavirales; three genera including 17 species
45 viruses are united in 17 species and three genera in the Nairoviridae family. The genera within the family form monophyletic clades based on RdRP, glycoprotein (GP), and N protein phylogeny. Genomes of viruses from all three genera have a similar genome architecture. Within the Orthonairovirus genus viruses have variable host ranges.
Genus Orthonairovirus. Five of the 14 species within this genus include viruses that have been isolated from birds or from ticks collected from birds: Crimean-Congo hemorrhagic fever orthonairovirus, Dera Ghazi Khan orthonairovirus, Hughes orthonairovirus, Sakhalin orthonairovirus, and Tamdy orthonairovirus.
Genus Orthonairovirus. Of the 14 species within this genus, viruses from all but two species (Hughes orthonairovirus and Sakhalin orthonairovirus) have been detected in mammals. Of those members with known vectors, most viruses are transmitted by ticks to mammalian hosts, such as bats, hares, rodents, and ungulates. Infections of their mammalian hosts are generally asymptomatic. An exception is Nairobi sheep disease virus (NSDV; species Nairobi sheep disease orthonairovirus), a tick-borne virus that occasionally causes lethal hemorrhagic gastroenteritis in small ruminants in Africa and India. One orthonairovirus, Crimean-Congo hemorrhagic fever virus (CCHFV, species Crimean-Congo hemorrhagic fever orthonairovirus), can infect humans and cause severe and frequently fatal disease. Although rare, Dugbe virus (DUGV, species Dugbe orthonairovirus), NSDV, and possibly Erve virus (ERVEV, species Thiafora orthonairovirus) infect and cause non-lethal disease in humans. Tamdy virus (TAMV) has been linked to a self-limiting acute fever that resolves in 5–7 days (L'vov et al., 1984b, Lvov 1994).The genus includes two species, Keterah orthonairovirus and Kasokero orthonairovirus, whose members are associated mainly with bats, and one species, Thiafora orthonairovirus, whose members have only been isolated from shrews (Walker et al., 2015).
Genus Orthonairovirus. This genus has virus members that replicate in hard (ixodid) and soft (argasid) ticks.
Genus Shaspivirus. This genus currently has one virus member, Shāyáng spider virus 1 (SySV-1), which was detected in spiders of 3 species (Li et al., 2015).
Genus Striwavirus. This genus currently has one virus member, Sānxiá water strider virus 1 (SxWSV-1), which was detected in gerrid water striders (Li et al., 2015).
Only known for members of the genus Orthonairovirus. Orthonairovirions are spherical in shape, 80–120 nm in diameter, the membrane envelope is decorated with GP spikes composed of GN and GC (Figure 1.Nairoviridae). Isolated ribonucleoprotein (RNP) complexes are composed of individual segment genomic RNA encapsidated in nucleoprotein (N). The nucleoproteins of Hazara virus (HAZV), kupe virus (KUPEV), Erve virus (ERVEV) and Crimean-Congo hemorrhagic fever virus (CCHFV) show structural conservation within the head domain of N (Surtees et al., 2015, Wang et al., 2015).
Figure 1.Nairoviridae. A) Electron micrograph of a Crimean-Congo hemorrhagic fever virus particle. Viral suspension was cleared by low speed centrifugation at 4,800 rpm for 10 min and the supernatant was centrifuged on the grid for 15 min at 100,000 xg. After washing in distilled water, the grid was negatively stained with 1% uranyl acetate. Photo details: Magnification 50, 000x. Microscope Jeol JEM 1400 Plus. (Courtesy of Mateja Poljšak-Prijatelj and Marko Kolenc, Institute of Microbiology and Immunology, Ljubljana, Slovenia. B) Schematic illustration of a nairovirus particle. Shown is the spherical and enveloped (grey) particle with glycoprotein spikes (GN yellow, GC blue) inserted in a bilaminar lipid envelope. The S (small), M (medium), and L (large) RNP (ribonucleoprotein) complexes inside the particle consist of N (nucleocapsid protein, green) and L (large protein, pink).
Only known for members of the genus Orthonairovirus. The virion Mr is 300×106 to 400×106 and has an S20,W of 350–500. Virion buoyant densities in sucrose and CsCl are 1.16–1.18 and 1.20–1.21 g cm−3, respectively. Virions are sensitive to heat, lipid solvents, detergents and formaldehyde.
Nairoviruses contain three negative-sense, single-stranded RNA segments. The three genomic segments are designated L (large), M (medium), and S (small). The viral mRNAs are not polyadenylated and contain a 5′-methylated cap and 10–18 non-templated nucleotides at the 5′-end that are derived from host cell mRNAs. Further information is only known for members of the genus Orthonairovirus. Orthonairoviruses contain the RNA segments in circular forms formed by non-covalent binding of the complementary and conserved 3′- and 5′-terminal sequences (9 nt). The Mr of the genome ranges from 4.8×106–8×106 and accounts for 1–2% of the weight of the virion.
Nairoviruses express 4 structural proteins (Table 2.Nairoviridae). The most abundant structural protein in a nairovirion is N (encoded by the S segment), which encapsidates the nairoviral genomic segments. The least abundant protein is L (encoded by the L segment), which mediates viral genome replication and transcription. Two glycoproteins, GN and GC, are encoded by the M segment. Specifics are only known for members of the genus Orthonairovirus.
Table 2.Nairoviridae. Location and function of orthonairovirus structural proteins.
Location, mass, and function
Structural virion protein (60–68 kD). Component of the RNP inside virions. Oligomerizes and encapsidates orthonairoviral genomic segments. Functions as an exoribonuclease.
Structural virion protein consisting of two subunits (GN 30–45 kD, GC 72–84 kD). Produced via proteolytic cleavage from the orthonairoviral genome-encoded precursor GPC. Cleavage produces GN, GC, and non-structural glycoproteins. Inserts into virion membranes as GP spikes composed of GN and GC. As a putative class I fusion protein, GP mediates cell-surface and internal receptor binding, virion-cell membrane fusion and, thereby cell entry.
Large protein (L)
Structural virion protein (250–450 kD) with RdRP, helicase, and endoribonuclease domains. Component of the RNP inside virions. Oligomerizes and mediates transcription and replication of orthonairoviral RNA segments. Contains an ovarian tumor family-like domain (OTU) that is conserved among all orthonairoviruses. Mediates cap-snatching for viral mRNA capping.
Nairoviruses encode three different proteins, in the virus-complementary sense RNA: S RNA encodes N, the M RNA encodes the viral GP precursor (GPC), and the L RNA encodes the large protein L, which has RNA-directed RNA polymerase, helicase, and endonuclease domains (Figure 2.Nairoviridae).). Based on experimental evidence from CCHFV, nairoviral glycoproteins (GN and GC) and non-structural glycoproteins of unknown function are derived by co-translational and post translational cleavage from an intracellular GP precursor (GPC) by cellular proteases (Bergeron et al., 2015, Sanchez et al., 2006, Vincent et al., 2003).
Figure 2.Nairoviridae. Schematic representation of nairovirus genome organization.
Specifics are only known for members of the genus Orthonairovirus Orthonairovirus infection starts with attachment to unknown cell-surface receptors and entry via the endosomal route (Garrison et al., 2013, Simon et al., 2009) (Figure 3.Nairoviridae). Viral fusion with the host cell results in early or late endosomal release, depending on the virus, of the virion RNP complex into the cytoplasm. This pH-dependent fusion event likely requires the previous participation of an intracellular receptor (Garrison et al., 2013, Shtanko et al., 2014). During primary transcription the virion-associated large protein (L) generates uncapped antigenomic RNA which are then capped using host-cell derived capped primers (Holm et al., 2018). L and S segment-transcribed mRNAs are translated by free ribosomes. M segment-transcribed mRNA is translated by membrane-bound ribosomes, co-translationally cleaved to yield GN and GC and non-structural glycoproteins and glycosylated by nascent envelope proteins. The synthesis of the antigenome RNA by the RdRP domain of the L protein serves as a template for genomic RNA replication. Secondary transcription amplifies the synthesis of mRNA and genome replication. During morphogenesis, GN and GC accumulate in the Golgi, are terminally glycosylated, modified host membranes are acquired, and virions bud into the Golgi cisternae (Booth et al., 1991, Rwambo et al., 1996).
Figure 3.Nairoviridae. Lifecycle of nairoviruses. (1) Virion attachment; (2) virion uptake; (3) virion-cell membrane fusion; (4) transcription; (5) translation; (6) replication; (7) virion assembly; and (8) virion egress.
Most viruses within this family are transmitted by ticks; a few viruses have been isolated from biting midges, horseflies, and mosquitoes, although the role of these hosts in virus transmission is not proven. One virus has been found by sequencing of RNA in spiders, one virus by sequencing of RNA in water striders, and one virus has been found by sequencing RNA in millipedes. Specifics are only known for members of the genus Orthonairovirus. Most orthonairoviruses are capable of alternately replicating in vertebrates and arthropods, and cause little or no cytopathogenicity in their invertebrate hosts. The viruses within this genus are transmitted by different species of hard (Ixodidae) and soft (Argasidae) ticks. Although a few viruses have been isolated from biting midges, horseflies, and mosquitoes, the role of these hosts in virus transmission is not proven. Transovarial, transstadial, and venereal transmission have been demonstrated for CCHFV. In general, the viruses of the same species have strictly limited range of the arthropod vectors and occupy a specific ecological niche. The range of vertebrate hosts is mainly determined by the ecology of their vectors and includes mammals, birds, and bats. The orthonairoviruses that are vectored by soft ticks infect rodents, birds, and bats, while species vectored by hard ticks infect mammals (small ruminants, hares, human, etc.) and birds. Among orthonairoviruses, only CCHFV is known as an important human pathogen causing severe form of haemorrhagic fever. However, there are several reports that Issyk-kul virus (L'vov et al., 1984a), Tamdy virus (L'vov et al., 1984b, Lvov 1994), Dugbe virus (Burt et al., 1996), and NSDV, can also cause mild febrile illness in humans.
Only known for members of the genus Orthonairovirus. One or both of the envelope glycoproteins display hemagglutinating and neutralizing antigenic determinants. Complement-fixing antigenic determinants are principally associated with the nucleoprotein.
Nairoviridae: from Nairobi (Kenya) where Nairobi sheep disease virus was first isolated, and viridae, suffix for a family.
The availability of at least coding-complete sequences of all genome segments may be sufficient for nairovirus classification in the absence of a cultured isolate.
Demarcation of genera is based upon considerations of their phylogenetic relationships, significant differences in member virus genome architecture, virion antigenicity, and virus ecology (e.g., host range, pathobiology, and transmission patterns). Three genera have been established to date.
Phylogenetic relationships across the family have been estimated using maximum likelihood trees generated from complete and partial protein sequences (Figure 4.Nairoviridae).
Figure 4A.Nairoviridae. Midpoint-rooted maximum likelihood phylogenetic trees inferred from (A - above) S, (B - Figure 4B.Nairoviridae below) M, and (C - Figure 4C.Nairoviridae below) L protein sequences. Three separate alignments, one for each segment’s coding sequence, were first aligned using MUSCLE version 3.8.425 (Edgar 2004) and manually curated in Geneious R9 (Kearse et al., 2012). Maximum likelihood trees were estimated with an exhaustive search (-slow), WAG amino acid substitution model (Whelan and Goldman 2001), 20 Γ-rate categories, and 1,000 bootstrap replications using FastTree 2.1 (Price et al., 2010). Tree rooting and visualization was done in FigTree (Rambaut 2020). Species with more than four representative sequences in a monophyletic clade were collapsed for simplicity. Bootstrap support values are shown at tree nodes as a percentage and only if greater than 70%. Tree branches are scaled by amino acid substitutions per site. GenBank accession numbers for nucleotide sequences are shown at tree tips. Circles at tips are colour-filled according to species; open circles indicate unclassified viruses. The Rondônia virus sequences are incomplete. These phylogenetic trees and corresponding sequence alignments are available to download from the Resources page.
Figure 4B.Nairoviridae. Midpoint-rooted maximum likelihood phylogenetic trees inferred from M protein sequences. See Figure 4A.Nairoviridae legend for full details. These phylogenetic trees and corresponding sequence alignments are available to download from the Resources page.
Figure 4C.Nairoviridae. Midpoint-rooted maximum likelihood phylogenetic trees inferred from L protein sequences. See Figure 4A.Nairoviridae legend for full details. These phylogenetic trees and corresponding sequence alignments are available to download from the Resources page.
Nairoviruses are most closely related to Wǔhàn millipede virus 2 (WhMV-2; Wupedeviridae) and, more distantly, to members of the families Arenaviridae and Mypoviridae (Wolf et al., 2018).
Additional unclassified nairoviruses that are probable members of existing genera are listed under individual genus descriptions.
S: MG880115; L: MG880120
Blattodean nairo-related virus OKIAV321
Not available (Käfer et al., 2019)
Finch Creek virus
S: KY700683; L: KY700684
Norway nairovirus 1
S: MF141045; L: MF141044
Pacific Coast tick nairovirus
S: KU933935; M: KU933934; L: KU933933
S: KT007143; L: KT007142
South Bay virus
S: KJ746878; L: KJ746877
Xīnzhōu spider virus
S: KM817762; M: KM817729; L: KM817702
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