Family: Nairoviridae

Genus: Orthonairovirus

Distinguishing features

There are 51 distinct viruses currently assigned to the genus Orthonairovirus. These viruses typically infect specific argasid or ixodid ticks, which transmit them to small vertebrates (birds and mammals) that in turn then server as sources for tick infection. Some orthonairoviruses are transmitted transovarially in ticks.

Virion

Morphology

Orthonairovirions are spherical in shape, 80–120 nm in diameter, and surrounded by a membrane envelope that is decorated with glycoprotein (GP) spikes composed of G_N and G_C subunits (Figure 1 Orthonairovirus). Isolated ribonucleoprotein (RNP) complexes are composed of individual segment genomic RNA encapsidated by nucleoprotein (N). Hazara virus (HAZV), kupe virus (KUPEV), Erve virus (ERVEV), and Crimean-Congo hemorrhagic fever virus (CCHFV) Ns are structurally conserved in the head domain (Korolev et al., 1976, Tantawi et al., 1980, Munz et al., 1981, Booth et al., 1991, Rwambo et al., 1996, Surtees et al., 2015, Wang et al., 2015).

Figure 1 Orthonairovirus. A) Electron micrograph of a Crimean-Congo hemorrhagic fever virus particle. Magnification 50 000× (Courtesy of Mateja Poljšak-Prijatelj and Marko Kolenc, Institute of Microbiology and Immunology, Ljubljana, Slovenia). B) Schematic illustration of an orthonairovirus 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 (nucleoprotein, green) and L (large protein, pink).

Physicochemical and physical properties

The virion Mr is 300×10⁶ to 400×10⁶ and has an S_20,W of 350–500. Virion buoyant densities in sucrose and CsCl are 1.16–2.0 and 1.20–1.21 g cm⁻³, respectively. Virions are sensitive to heat, lipid solvents, detergents, and formaldehyde (Donets et al., 1977, Terpstra 1983).

Nucleic acid

Orthonairovirus genomes are linear trisegmented RNA molecules of negative polarity. The genomes are about 17.2–20.1 kb (small [S] segment: 1.4–3.8 kb; medium [M] segment: 3.9–5.9 kb; large [L] segment: 11.7–12.6 kb) (Obijeski and Murphy 1977, Clerx et al., 1981, Kuhn et al., 2016, Alkhovsky et al., 2017, Kapuscinski et al., 2021). The Mr of the genome ranges from 4.8×10⁶–8×10⁶ and accounts for 1–2% of the weight of the virion (Bishop et al., 1980, Clerx et al., 1981).

Proteins

Orthonairoviruses typically express three structural proteins (Table 1 Orthonairovirus). The most abundant structural protein in an orthonairovirion is N, which encapsidates the orthonairoviral genomic segments. The least abundant protein is L, which mediates viral genome replication and transcription. Two glycoprotein subunits, G_N and G_C, mediate virion entry. G_N and G_C and non-structural proteins (encoded by some, but not all orthonairoviruses (Freitas et al., 2020)) are encoded as a precursor polyprotein.

Table 1 Orthonairovirus. Location and function of orthonairovirus structural proteins.

Genome organization and replication

The orthonairovirus genome consists of three negative-sense RNA molecules, termed S (small), M (medium), and L (large) (Figure 2 Orthonairovirus).

Figure 2 Orthonairovirus. Schematic representation of orthonairovirus genome organization.

Orthonairovirus genomic segments assume circular forms via non-covalent binding of complementary and highly conserved 3′-and 5′-terminal sequences (11 nt at the extreme ends). The consensus terminal nucleotide sequences of the S, M, and L segments are typically characterized by a genus-specific 5′-genomic segment terminus 5′-UCUCAAAGA-3′ and 3′-genomic segment terminus of 5′-UCUUUGAGA-3′. The nairovirid, and hence orthonairovirus, promoters are unique among bunyavirals. They are bipartite and are located within the complementary terminal segment regions that include these 11 nts (promoter element 1 [PE1]) and adjacent segment-specific nucleotide stretched (PE2) (Matsumoto et al., 2019, Mega et al., 2020, Neriya et al., 2022). Genomic segment reassortment occurs among viruses belonging to the same species but not among viruses of different species.

Orthonairovirus infection starts with virion attachment, mediated by G_N and G_C, to unknown cell-surface receptors and entry via the endosomal route (Simon et al., 2009, Garrison et al., 2013, Shtanko et al., 2014) (Figure 3 Orthonairovirus).

Figure 3 Orthonairovirus. Lifecycle of orthonairoviruses. (1) Virion attachment; (2) virion uptake; (3) virion-cell membrane fusion; (4) transcription; (5) translation; (6) replication; (7) virion assembly; and (8) virion egress.

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 L generates uncapped antigenomic RNA that are then capped using host-cell derived capped primers (cap snatching) (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, with the expressed GPC co-translationally and post-translationally cleaved by cellular proteases and glycosylated by cellular glycosidases to yield G_N and G_C and sometimes non-structural glycoproteins. The synthesis of the antigenomic by L protein serves as a template for genomic RNA replication. Secondary transcription amplifies the synthesis of mRNAs and genome replication. During morphogenesis, G_N and G_C accumulate in the Golgi apparatus, modified host membranes are acquired, and virions bud into the Golgi cisternae (Booth et al., 1991, Rwambo et al., 1996, Vincent et al., 2003, Sanchez et al., 2006, Bergeron et al., 2015).

Biology

Most orthonairoviruses are capable of alternately replicating in arthropods (argasid or ixodid ticks) and vertebrates (alcid, larid, or struthionid birds; hipposiderid, molossid, pteropodid, and verspertillionid bats; soricid eulipotyphla; lagomorphs; murid rodents, pangolins (Pholidota); or ungulates), and cause little or no cytopathogenicity in their hosts (Spengler et al., 2016). Transovarial, transstadial, and venereal transmission have been demonstrated for CCHFV. In general, distinct orthonairoviruses have a strictly limited range of arthropod vectors and occupy a specific ecological niche. The range of vertebrate hosts is mainly determined by the ecology of their vectors. The most important human orthonairovirus with public-health impact is CCHFV, which is tick-borne and endemic in much of Asia, Africa, and Southern and Eastern Europe, where it causes often severe and frequently fatal viral hemorrhagic fever (Pigott et al., 2017, Blair et al., 2019, Belobo et al., 2021, Temur et al., 2021, Fereidouni et al., 2023, Hawman and Feldmann 2023). Other viruses causing occasional disease in humans are Aigai virus (AIGV; febrile disease, viral hemorrhagic fever) (Midilli et al., 2009, Salehi-Vaziri et al., 2016, Papa et al., 2022), Dugbe virus (DUGV; febrile disease) (Georges et al., 1980, Burt et al., 1996), ERVEV (thunderclap headache) (Treib et al., 1998), Issyk-kul virus (ISKV; febrile disease) (L'Vov D et al., 1980, L'Vov D et al., 1984a), Kasokero virus (KASV; febrile disease) (Kalunda et al., 1986), Nairobi sheep disease virus (NSDV [discouraged synonym: Ganjam virus]; febrile illness) (Dandawate et al., 1969, Rao et al., 1981, Baron and Holzer 2015), Soldado virus (SOLV; febrile disease) (Chastel et al., author's transl, Chastel et al., 1981b), Sōnglǐng virus (SGLV; febrile disease) (Ma et al., 2021), Tǎchéng tick virus 1 (febrile disease) (Liu et al., 2020, Zhang et al., 2021), Tamdy virus (L'Vov D et al., 1984b, Lvov 1994, Moming et al., 2021), and Yezo virus (YEZV; febrile disease) (Rao et al., 1981, Kodama et al., 2021). The most significant orthonairovirus with veterinary importance is NSDV, which is also tick-borne and causes lethal hemorrhagic gastroenteritis in small ruminants in Africa and India (Baron and Holzer 2015, Krasteva et al., 2020). Another orthonairovirus of veterinary importance is Soldado virus (SOLV), which causes lethal infections in juvenile marine birds (Converse et al., 1975b, Chastel et al., author's transl, Chastel et al., 1981b, Chastel et al., 1990).

Antigenicity

One or both of the envelope glycoprotein subunits have hemagglutinating and neutralizing antigenic determinants. Complement-fixing antigenic determinants are principally associated with the nucleoprotein (Shope 1985, Elliott 1990, Bertolotti-Ciarlet et al., 2005).

Species demarcation criteria

Members of different species in the genus are <93% identity in L amino-acid sequence.

Phylogenetic relationships

Phylogenetic relationships across the genus have been estimated using maximum likelihood trees generated from complete N, GPC, and L amino-acid sequences (Figure 2 Nairoviridae).

Related, unclassified viruses

Virus names and virus abbreviations are not official ICTV designations.

*Coding region sequence incomplete.