A Look into Bunyavirales Genomes: Functions of Non-Structural (NS) Proteins

Abstract

In 2016, the Bunyavirales order was established by the International Committee on Taxonomy of Viruses (ICTV) to incorporate the increasing number of related viruses across 13 viral families. While diverse, four of the families (Peribunyaviridae, Nairoviridae, Hantaviridae, and Phenuiviridae) contain known human pathogens and share a similar tri-segmented, negative-sense RNA genomic organization. In addition to the nucleoprotein and envelope glycoproteins encoded by the small and medium segments, respectively, many of the viruses in these families also encode for non-structural (NS) NSs and NSm proteins. The NSs of Phenuiviridae is the most extensively studied as a host interferon antagonist, functioning through a variety of mechanisms seen throughout the other three families. In addition, functions impacting cellular apoptosis, chromatin organization, and transcriptional activities, to name a few, are possessed by NSs across the families. Peribunyaviridae, Nairoviridae, and Phenuiviridae also encode an NSm, although less extensively studied than NSs, that has roles in antagonizing immune responses, promoting viral assembly and infectivity, and even maintenance of infection in host mosquito vectors. Overall, the similar and divergent roles of NS proteins of these human pathogenic Bunyavirales are of particular interest in understanding disease progression, viral pathogenesis, and developing strategies for interventions and treatments.

Keywords: bunyavirales; hantaviridae; interferon antagonist; nairoviridae; non-structural proteins; peribunyaviridae; phenuiviridae.

Figure 1

Bunyavirales Phylogenetic Tree. Order Bunyavirales phylogenetic tree based on nucleoprotein amino acid sequences of the 13 families. Families for which a specific virus is not listed are arranged via analysis of type species as listed in Table 1. Specific vector species are depicted for Nairoviridae (mosquito, tick), Peribunyaviridae (mosquito), Arenaviridae (rodent), Hantaviridae (rodent), and Phenuiviridae (sandfly, mosquito, tick). While these families may contain viruses transmitted through other vectors, these illustrations represent those of the viruses listed and discussed in this review. The phylogenetic tree was constructed using S segment nucleoprotein amino acid sequences from Genbank and was assembled using Geneious Prime tree builder global alignment with free end gaps, cost matrix PAM250, genetic distance model Jukes-Cantor, tree build method neighbor-joining, and no outgroup. The resulting tree was transformed so that branches are of equal length. Tree segments are not to scale. Genbank accession numbers for sequences used: Mypoviridae (NC_033760.1), Wupedeviridae (NC_043501.1), Nairoviridae (MH483984.1, FJ422213.2, MH791451.1, NC_038711.1, JF911699.1), Tospoviridae (MN861976.1), Peribunyaviridae (MH484290.1, MT276603.1, MH830340.1, MT022508.1, KM507341.1, MK896460.1, MK330166.1, NC_043673.1, LC552050.1), Arenaviridae (MG554174.1, MG189700.1, MT861994.1), Hantaviridae (MN258229.1, MT514275.1, MN832781.1, MN657233.1, MK360773.1, MT012546.1, KT885046.1), Leishbuviridae (KX280017.1), Phenuiviridae (DQ380149.1, NC_018137.1, NC_024496.1, EF201835.1, MT032306.1, KM114248.1, NC_043610.1, HM566145.1, EF201822.1), Cruliviridae (NC_032145.1), Fimoviridae (LR536377.1), Phasmaviridae (NC_043032.1), and Unassigned (MG764564.1).

Figure 2

Bunyavirales Generalized Virion. Although bunyaviruses can vary in number of genomic segments and glycoprotein dimer structure, all viruses share a similar structure. Nucleocapsid proteins coat the single-stranded anti-sense RNA genomes and along with the RNA-dependent RNA-polymerase form ribonucleoproteins on each segment. The genomic segments are packaged in an enveloped virion studded with the viral glycoproteins. The genomic small, medium, and large segments are labeled S, M, and L, respectively.

Figure 3

Bunyavirales Genome Organization. Specific genome structures for Bunyavirales families containing human pathogens, including Arenaviridae, Peribunyaviridae, Nairoviridae, Hantaviridae, and Phenuiviridae [5,12,13,14,15,16,17,18,19], are shown. The reference strain for each family is listed as well as the approximate size of each genomic segment. Glycoprotein precursor (GPC), nucleoprotein (NP), intergenic region (IGR), zinc-binding matrix protein (Z), non-structural S segment protein (NSs), non-structural M segment protein (NSm), surface glycoproteins (Gn and Gc), mucin-like domain (MLD), and secreted glycoprotein (GP38). NS proteins are highlighted in dark blue and include NSs and NSm, along with MLD and GP38 for Nairoviridae. The L segment is not as well understood as S and M and has many regions with unknown function but, across the order encodes the RNA-dependent RNA-polymerase (RdRp) gene.