key: cord-010374-z9ygudv6
authors: Siddell, S.G.; Anderson, R.; Cavanagh, D.; Fujiwara, K.; Klenk, H.D.; Macnaughton, M.R.; Pensaert, M.; Stohlman, S.A.; Sturman, L.; van der Zeijst, B.A.M.
title: Coronaviridae1
date: 2008-07-24
journal: Intervirology
DOI: 10.1159/000149390
sha: 
doc_id: 10374
cord_uid: z9ygudv6

The family Coronavirtdae comprises a monogeneric group of 11 viruses which infect vertebrates. The main characteristics of the member viruses are: (i) Morphological: Enveloped pleomorphic particles typically 100 nm in diameter (range 60-220 nm), bearing about 20 nm long club-shaped surface projections, (ii) Structural: A single-stranded infectious molecule of genomic RNA of about (5-7) × 10(6) molecular weight. A phosphorylated nucleocapsid protein [mol.wt. (50-60) × 10(3)] complexed with the genome as a helical ribonucleoprotein; a surface (peplomer) protein, associated with one or two glycosylated polypeptides [mol.wt. (90-180) × 10(3)]; a transmembrane (matrix) protein, associated with one polypeptide which may be glycosylated to different degrees [mol.wt. (20-35) × 10(3)]. (iii) Replicative: Production in infected cells of multiple 3′ coterminal sub genomic mRNAs extending for different lengths in the 5′ direction. Virions bud intracytoplasmically. (iv) Antigenic: 3 major antigens, each corresponding to one class of virion protein, (v) Biological: Predominantly restricted to infection of natural vertebrate hosts by horizontal transmission via the fecal/oral route. Responsible mainly for respiratory and gastrointestinal disorders.

Since the second report of the Coronavirus Study Group in 1978 [1] , considerable data, especially on the structure and replication of coronaviruses, have been published, and we feel a new report is justified. The Corona viridae are a monogeneric family of pleo morphic, ether-labile, enveloped viruses. The virions have a diameter ranging from 60 to 220 nm and an average density in sucrose of 1.18 g/nil. They characteristically bear clubshaped surface projections about 20 nm in length from which the group derives its name (Latin corona, crown) [1] , The genomic RNA is an infectious single-stranded molecule which is capped and polyadenylated. The molecular weight is between 5x 106 and 7* 10°, cor responding to about 15,000-20,000 nucleo tides. There is no extensive sequence reiter ation in the coronavirus genome. Coronavirions characteristically have three types of protein: a phosphorylated nucleocapsid pro tein [mol.wt. (50-60) x 103], complexed with the genome as a helical ribonucleoprotein (RNP); an jV-glycosylated surface peplomer protein, associated with glycopolypeptides of (90-180) x 103 molecular weight, which isacylated and is responsible for virus attachment and cell-to-cell fusion (this protein may be removed by protease treatment); and a trans membrane matrix protein, associated with polypeptides of molecular weight (20-35) x 103 which have variable degrees of glycosylation. In the case of murine and bovine coronaviruses this polypeptide bears O-glycosidically linked oligosaccharides, and in the case of avian infectious bronchitis virus it bears Nglycosidically linked oligosaccharides.

Most coronaviruses replicate in tissue cul ture within 12 h at 37°. Infection is often accompanied by cytopathic changes. There are conflicting reports as to whether a nuclear function is required for coronavirus replica tion. There are few data about the early events (adsorption, penetration, uncoating, etc.) in volved in coronavirus replication. It is as sumed that upon entering the cell the positivestranded genome encodes protein(s) whose function is to replicate the genomic RNA and produce subgenomic mRNA. Recently, there have been reports of virus-specific RNA poly merases in coronavirus-infected cells, but the components of the enzyme have not been iden tified. Characteristic of coronavirus infection is the production of 3' coterminal subgenomic RNAs which form a nested set extending in a 5' direction. These RNAs are capped and poly adenylated. The replicative structures from which they are produced have not been char acterized, but it has been demonstrated that the negative-stranded template from which murine hepatitis virus mRNAs are copied is of genome length. UV inactivation studies in dicate that coronavirus mRNAs are not pro duced by the processing of a larger RNA, although extensive sequence homologies have been detected at the 5' ends of ail murine hepatitis virus-specific subgenomic RNAs. For murine hepatitis virus, the mRNA function of each of the subgenomic viral RNAs has been demonstrated in vitro, and the mRNAs encod ing each of the virion proteins, or its precur sors, have been identified ( fig. 1 ). Comparing the size of each mRNA with its translation product suggests that the expressed informa tion lies within the 5' sequences of each RNA which are not found in the next smallest RNA. For murine hepatitis virus, glycosylation of the peplomer protein is initiated cotranslationally in the rough endoplasmic reticulum, whereas the transmembrane protein is glyco sylated posttranslationally in the Golgi ap paratus. The infectious bronchitis virus matrix protein is glycosylated on the nascent poly peptide. After synthesis, genomic RNA and virion proteins are assembled at the rough endoplasmic reticulum and virions bud into cisternae, acquiring their lipid membranes from the cell. The virions are subsequently transported to and accumulate in Golgi and smooth-walled vesicles. There is an absence of budding from the plasmaiemma. The mecha nism of virus release has not been character ized. No difference be tween the genome RNA and mRNA 1 has yet been de scribed. Each mRNA encodes only one protein, and the translation products of mRNAs 7, 6 and 3 have been identified as the intracellular precursors to the virion nucleocapsid, matrix and peplomer proteins, respectively. As the size of the translation product for each mRNA corresponds approximately to the coding potential of the 5' sequences which are absent from the next smallest mRNA, it seems likely that only these regions are translated into protein.

The relationships between some coronaviruses have been studied by molecular and immunological methods, but the data are frag mentary. Molecular hybridization indicates extensive sequence homology (about 70%) between murine hepatitis virus strains, in par ticular within the gene encoding the nucleo capsid protein. This conclusion is supported by oligonucleotide fingerprinting of genomic RNAs and chymotryptic peptide fingerprint ing of nucleocapsid proteins. Oligonucleotide fingerprinting of the genomic RNA of a num ber of infectious bronchitis virus strains in dicates greater sequence divergence both be tween and within serotypes of this species. Coronaviruses contain 3 major antigens which can be distinguished by antibodies against virion subcomponents. Each antigen corre sponds to one of the three types of corona-virus protein. Immunological studies with monoclonal antibodies, antisera directed against subcomponents prepared from puri fied virions, and immune electron microscopy indicate that the antigenic sites responsible for the induction of neutralizing antibodies are associated with the surface peplomer polypeptide(s). Studies on the antigenic relationships of coronaviruses present a complex pattern. Relationships have been determined by a wide variety of tests, mainly using polyvalent sera from naturally infected or hyperimmunized animals. These immunological studies indicate that there are two antigenic groups of mam malian coronaviruses and two antigenic groups of avian coronaviruses. One recent porcine isolate does not appear to fall into either mam malian group. Many viruses remain to be clas sified.

The geographic distribution of many coronaviruses is known to extend over several con tinents and is probably worldwide. A seasonal incidence of infection occurs with some viruses, namely human coronavirus and transmissible gastroenteritis virus. Coronaviruses predomi nantly infect their natural vertebrate hosts. Biological vectors of coronaviruses have not been reported, and the natural hosts form the major reservoirs for further infection. In most cases, infection is by the fecal/oral route. Ver tical intrauterine infection has been reported for infectious bronchitis virus and some murine hepatitis virus strains. Transmission from con taminated clothing and equipment is an im portant source of infection with infectious bronchitis virus and bovine coronavirus. Co ronaviruses are associated with diseases of economic and clinical importance, predomi nantly respiratory and gastrointestinal dis orders. Feline infectious peritonitis virus is responsible for peritonitis in cats, and hemag-glutinating encephalomyelitis virus and some murine hepatitis virus strains are associated with encephalomyelitis. Diagnosis of corona virus infection is initially clinical, and confir mation is most readily achieved by virus isola tion and propagation in vitro and/or by a variety of immunological procedures [2] , At present the family Coronaviridae is re cognized as 11 species, which are listed below. A number of recent isolates meet the morpho logical and, to some extent, the molecular cri teria for inclusion in the group, but are as yet insufficiently characterized to be regarded as 'possible' family members. The question of speciation and whether the family should remain monogeneric will be considered by the Study Group in the near future. This report does not contain references to primary sources. Extensive bibliographies can be found in several recent reviews of coronavirus biol ogy [3] [4] [5] [6] . The acronyms used throughout this report are defined in section 10.3. The classification of other isolates re quires further information. In parti cular, further evidence is required to determine whether HECV, included in the previous report [ I ] as a corona virus, is indeed a coronavirus. The problem of the characterization of HECV has been discussed in a recent review [7] .

Coronaviridae: second report

Coronaviruses: diagnosis of infections. Comp. Diagn. viral Dis

The struc ture and replication of coronaviruses

The biol ogy of coronaviruses

The molecular biol ogy of coronaviruses

The biology and pathogenesis of coronaviruses

Human en teric coronaviruses