A nidovirus perspective on SARS-CoV-2

Abstract

Two pandemics of respiratory distress diseases associated with zoonotic introductions of the species Severe acute respiratory syndrome-related coronavirus in the human population during 21st century raised unprecedented interest in coronavirus research and assigned it unseen urgency. The two viruses responsible for the outbreaks, SARS-CoV and SARS-CoV-2, respectively, are in the spotlight, and SARS-CoV-2 is the focus of the current fast-paced research. Its foundation was laid down by studies of many corona- and related viruses that collectively form the vast order Nidovirales. Comparative genomics of nidoviruses played a key role in this advancement over more than 30 years. It facilitated the transfer of knowledge from characterized to newly identified viruses, including SARS-CoV and SARS-CoV-2, as well as contributed to the dissection of the nidovirus proteome and identification of patterns of variations between different taxonomic groups, from species to families. This review revisits selected cases of protein conservation and variation that define nidoviruses, illustrates the remarkable plasticity of the proteome during nidovirus adaptation, and asks questions at the interface of the proteome and processes that are vital for nidovirus reproduction and could inform the ongoing research of SARS-CoV-2.

Keywords: Comparative genomics; Coronaviruses; Evolution; Nidoviruses; Proteome.

Fig. 1

SARS-CoV genome organization and expression. Genome (top), products of genome translation (left) and transcription (right) are shown. ORFs and polyprotein regions are colored according to their predominant function (see inset). Genome ORFs are depicted in their frame, with ORF1a frame set to zero. For each sg mRNA, only ORFs believed to be translated from it are shown, without indicating their frame relative to ORF1a. For genome and sg mRNAs, RNA signals are indicated by color (see inset). For polyproteins, autoproteolytic processing scheme (see inset) and selected protein domains (see text for abbreviations) are specified. The NC_004718.3 record was used to prepare this figure. Note that sg mRNA 3.1 [55] is not shown; the most N-terminal ubiquitin (Ub) and Macro domains are separated by acidic, structurally disordered region of ∼70 aa [56,57]. SUD-N and SUD-M, N-terminal and Middle domains of SARS-CoV Unique Domain, respectively [58,59]; Y, Y domain [57].

Fig. 2

Nidoviruses with canonical (SARS-CoV) and non-canonical genome ORFs organization. WJHAV, Wuhan Japanese halfbeak arterivirus (MG600020.1), species Halfbeak nidovirus 1, family Nanhypoviridae; BNV1, Beihai nido-like virus 1 (KX883629.1), species Turrinivirus 1, family Medioniviridae; AAbV, Aplysia abyssovirus 1 (GBBW01007738.1), species Aplysia abyssovirus 1, family Abyssoviridae; PSCNV, planarian secretory cell nidovirus (MH933735.1), species Planidovirus 1, family Mononiviridae. ORFs are positioned according to their reading frame, with the most 5′-terminal depicted ORF set as zero. ORF regions are colored according to their main function assignment (see inset). Genome signals, described by the discoverers of each virus, are indicated by color (see inset).

Fig. 3

Phylogeny and pp1ab domain organization of selected nidoviruses. Representatives of 13 lineages of nidoviruses that infect vertebrates (three virus families) and invertebrates (two virus families) are depicted. Names of taxa, families and genera, are indicated in grey italic font, and names of viruses are given as acronyms: EAV, equine arteritis virus; SHFV, simian hemorrhagic fever virus; LDV, lactate dehydrogenase-elevating virus; PRRSV, porcine reproduction respiratory syndrome virus; BRV, Breda virus; WBV, white bream virus; "BPNV, ball python nidovirus;" TGEV, porcine transmissible gastroenteritis virus; MHV, mouse hepatitis virus; BuCoV_HKU11, bulbul coronavirus HKU11; IBV, avian infectious bronchitis virus; NDiV, Nam Dinh virus; GAV, gill-associated virus. Midpoint rooted phylogeny was reconstructed based on Viralis multiple sequence alignment [92] of the conserved core of RdRp, using IQ-Tree 1.5.5 [93] with automatically selected the rtREV + F + I + G4 evolutionary model. To estimate branch support, SH-like approximate likelihood ratio test with 1000 replicates was conducted. Polyproteins pp1ab are shown as light grey bars; they are autoproteolytically processed to nsps that were identified only for few nidoviruses and omitted here (see also Fig. 1). TM domains are shown as dark grey bars; TM helices were predicted by TMHMM2.0c [94] and clustered if separated by less than 300 aa (less than 180 aa for arteri- and tobaniviruses). Other selected domains, whose coordinates were obtained from the Viralis database [92], are shown as colored bars; proteolytically inactive PLP domains are indicated by stripes on bars; indices of PLP domains are specified below the bars. "Pkinase, protein kinase [25]; CPD, cyclic phosphodiestarase known also as 2′,5′-phosphodiesterase, 2′PDE [58,95]; NADAR, domain involved in the utilization of NAD and ADP-ribose derivatives [96]; for other domains, see Fig. 1 and the text."

Fig. 4

Capping pathway and enzymes in relation to the proteome of nidoviruses. The conventional mRNA capping pathway is shown on the left, with the enzymes catalyzing the respective four reactions listed in bold. Further to the right, presence of these enzymes in viruses of five nidovirus families, each designated by its prefix, is listed (see Fig. 3 for phylogeny and pp1ab domain organization). RTPase, 5′-triphosphotase; GTase, guanylyl transferase; N-MT, guanine-N7-methyltransferase; O-MT, 2′-O-methyltransferase. In ^m7GpppN_2’-Om notation, ^m7G stands for 7-methylguanosine, p stands for phosphate, N_2’-Om stands for the 5′-terminal nucleoside of the RNA molecule, methylated at the ribose-2′-O position. For details, see text.

Fig. 5

Proposed roles of PSCNV ANK and its host homologs in modulation of antiviral immune response. (A) In the non-infected cells, NF-ĸB protein (SMU15016868) resides in the cytoplasm, bound by inhibitors: its own ANK domain and protein IκB (SMU15003987). (B) In response to viral infection, inhibitors are degraded, allowing the NF-κB transcription factor to enter the nucleus and modulate gene expression to promote antiviral immune response. (C) IκB-mimicking viral protein (PSCNV ANK) may retain the NF-κB transcription factor in the cytoplasm after its inhibitors were degraded, thus downregulating the immune response.