Michelle Hsiang's
Coronaviridae Webpage

Issues of Classification
Historical Notes
Unique Replication
Recent Updates
Useful web links

The following webpage was created as part of an ongoing project in Humans and Viruses, a class taught by Dr. Robert Siegel through the Human Biology Department at Stanford University. Each student is responsible for creating a webpage pertaining to a certain human virus family. My webpage serves as an addendum to Radika's Coronaviridae webpage created last year. Click here to look at webpages created by other students.

Issues of Classification

How is a virus classified in the Coronaviridae family?
To be classified in the Coronaviridae family, a virus must fulfill the following criteria:

+ +, nonsegmented genome of about 30,000 nucleotides
+ genome consists of a large RNA polymerase gene, a large surface glycoprotein gene, a membrane protein gene, and a nucleocapsid protein gene arranged respectively in the 5' to 3' direction
+ virion envelope has large surface projections composed of glycoprotein
+ an integral membrane protein has characteristic three membrane-spanning regions in the amino-terminal half
+ produce a 3' coterminal set of four or more intracellular subgenomic mRNAs. Only the open reading frames (ORFs) at the 5' unique region of each mRNA are expressed
+ RNA polymerase is composed of two overlapping ORFs

How do you distinguish between coronaviruses and toroviruses?

+ Size of the nucleocapsid protein: Corona is about 60kDA and Toro is about 18 kDA
+ Shape of helical nucleocapsid structure: Corona is extended and Toro is tubular
+ No leader sequence at the 5' end of torovirus mRNAs
+ Coronavirus and torovirus gene products have dissimilar gene products

1912 First coronavirus-related disease to be recorded was feline infectious peritonitis
1937 Coronavirus first isolated from chickens
1965-1967 Realized that coronavirus was responsible for a human disease, the common cold
1968 Recognized as a group of enveloped, RNA viruses See "Historical Notes" below.
1972 A virus (later to be called torovirus) was isolated from a horse that had died of a severe diarrhea in Berne, Switzerland. Similar viruses were found in Swiss cattle and horse populations, but the virus seemed unrelated to any known virus.
1975 Accepted by the International Committee on the Taxonomy of Viruses as a separate family, the Coronaviridae
1978 Evident that the coronavirus genomic RNA was infectious
1983 A framework of the coronavirus replication strategy had been perceived
1987 Torovirus proposed as a new virus family by Marian Horzinek.
1992 Toroviruses included as a second genus in the Coronaviridae

Historical Notes

Discoveries leading up to group classification:

In 1965, Tyrrell and Bynoe isolated a virus from the nasal washings of a child showing typical symptoms of the common cold. The washings were found to induce common cold symptoms in volunteers, and the virus (named B814 after the number of the nasal washing) was sucessfully cultivated in human embryo tracheal organ tissue. In 1966, Hamre and Procknow worked at characterizing five "new" cold causing agents isolated from medical students. One of these "new" agents, the 229E strain, was successful grown in WI-38 cells. In the following year, Almeida and Tyrell showed that these isolates were morphologically identical to avian bronchitis and mouse hepatitis viruses. That same year, McIntosh et al isolated six morphologically similar viruses and grew them in organ cultures. Two of these isolates, OC 38 and 43 (OC standing for "organ culture"), were adapted to grow in suckling mice brain. Finally in 1968, the name coronaviruses was accepted to describe the characteristic morphology of these viruses (crown shaped EM appearance).

Controversy over creating the torovirus genus

The pleomorphic, enveloped, peplomer-bearing particles, that would later be called toroviruses, were first described by Weiss and Woode in the early 1980s. Further studies revealing morphological and antigenic differences suggested new classification. Toroviruses were found to have similar genome sequence and replication mechanism as coronaviruses. In 1992, a new genus was named when molecular characterization of Berne virus (BEV) showed an evolutionary link between the corona- and toroviruses.

Unique Replication

1. Coronaviruses attach to receptors on the membranes of target cells via a hemaggluttinin (glycoprotein E3 or E2).

2. Direct translation of the plus sense RNA occurs in the cytoplasm to yield an RNA dependent RNA polymerase. This polymerase is composed of two polyproteins translated from the 5' two-thirds of the. Because the genomic information for the two polyproteins overlap, translational frame-shifting occurs.

3. RNA polymerase helps transcribe a full-length minus sense RNA, which serves as a template for new plus strands and a group of 3' nested set of subgenomic mRNAs.
a. The nested set consists of 7 overlapping +sense mRNAs (one genomic, 6 subgenomic) that share a common 5' leader sequence and extend for different lengths from a common 3' end.
b. The polymerase first transcribes the leader sequence (72-77 nucleotides) from the 3' end of the minus sense antigenome.
c. The capped leader RNA dissociates from the template and reassociates with a complementary sequence to start copying the template through to its 5' end Each product is unique because only the unique sequence toward the 5' end is translated.

4. Envelope protein M is directed to the cisternae of the endoplasmic reticulum and the Golgi complex. Virions bud from the regions.

5. Virions are transported in vesicles to the plasma membrane for exocytosis.

Things to keep in mind:
+ 5' capped, 3' polyadenylated
+ Genetic recombination occurs at a high frequency between genomes of different coronaviruses; 25% of progeny during coinfection are recombinants
+ Replication does not require host transcription, and can occur in enucleated cells

Summary: Three unique features of coronavirus replication:
+ Nested transcripts
+ Discontinuous transcription makes the 5' segment of each nested transcript the same.
+ The 5' end of the viral genome contains two overlapping reading frames (ORFs) which are translated by ribosomal frame-shifting.

Diagram of Coronaviridae replication
+ NS=non structural proteins
+ E1=transmembrane glycoprotein
+ E2=peplomer glycoprotein
+ N=nucleoprotein
+ HE(E3)=hemagglutinin-esterase glycoprotein

Recent Updates

+ Persistent infection promotes cross-species transmissibility of mouse hepatitis virus (including humans).

Baric RS. Sullivan E. Hensley L. Yount B. Chen W. Persistent infection promotes cross-species transmissibility of mouse hepatitis virus. Journal of Virology. 73(1):638-49, 1999 Jan.

Chen W. Yount B. Hensley L. Baric RS. Receptor homologue scanning functions in the maintenance of MHV-A59 persistence in vitro. Advances in Experimental Medicine & Biology. 440:743-50, 1998

+ Cleavage sites of the two large polyproteins in human coronavirus 229E differ significantly with regard to their susceptibilities to proteolysis by a 3C-like proteinase (3CLpro). There also might be association of these polypeptides with intracellular membranes.

Ziebuhr J. Siddell SG. Processing of the human coronavirus 229E replicase polyproteins by the virus-encoded 3C-like proteinase: identification of proteolytic products and cleavage sites common to pp1a and pp1ab. Journal of Virology. 73(1):177-85, 1999 Jan.

+ protein sequence comparisons were made to divide coronaviruses into two groups which roughly reflect the taxonomic groups.

Tobler K. Ackermann M. Comparison of the di- and trinucleotide frequencies from the genomes of nine different coronaviruses. Advances in Experimental Medicine & Biology. 440:801-4, 1998.

+ Aminopeptidase N (APN) acts as a common receptor for human coronavirus HCV-229E and porcine transmissible gastroenteritis virus (TGEV), both members of coronavirus group I. Feline APN (fAPN) was shown to be a functional receptor for each of these coronaviruses in group I. Cats could serve as a "mixing vessel" in which simultaneous infection with several group I coronaviruses could lead to recombination of viral genomes.

Tresnan DB. Holmes KV. Feline aminopeptidase N is a receptor for all group I coronaviruses. Advances in Experimental Medicine & Biology. 440:69-75, 1998.

+ Human coronavirus 229E (HCV 229E) was found distinct from the other serogroup I coronaviruses: determinants that mediate infection of HCV 229E are found within the N-terminal parts of the human and feline APN proteins. Those that mediate the infection of transmissible gastro-enteritis virus (TGEV), feline infectious peritonitis virus (FIPV) and canine coronavirus (CCV) are located within the C-terminal parts of porcine, feline and canine APN respectively.

Kolb AF. Hegyi A. Maile J. Heister A. Hagemann M. Siddell SG. Molecular analysis of the coronavirus-receptor function of aminopeptidase N. Advances in Experimental Medicine & Biology. 440:61-7, 1998.

+ Expression of IgG or IgA virus neutralizing antibodies found to interfere with coronavirus infection.

Sola I. Castilla J. Enjuanes L. Interference of coronavirus infection by expression of IgG or IgA virus neutralizing antibodies. Advances in Experimental Medicine & Biology. 440:665-74, 1998.

+ Lactogenic immunity in transgenic mice producing recombinant antibodies neutralizing coronavirus.

Castilla J. Sola I. Pintado B. Sanchez-Morgado JM. Enjuanes L. Lactogenic immunity in transgenic mice producing recombinant antibodies neutralizing coronavirus. Advances in Experimental Medicine & Biology. 440:675-86, 1998.

+ Human macrophages found susceptible to coronavirus OC43.

Collins AR. Human macrophages are susceptible to coronavirus OC43. Advances in Experimental Medicine & Biology. 440:635-9, 1998.

Useful web links

+ General Replication Strategies for RNA Viruses

+ Coronaviruses- A Tutorial from the University of Leicester (UK)

+ Visit thewebpage of Susan C. Baker, Ph.D., a molecular virologist who is doing research on the molecular biology and pathogenesis of coronaviruses

+ To learn about coronavirus multiplication strategies (particularly virion assembly and mechanisms of viral RNA replication and transcription), look at the webpage of Shinji Makino Ph.D. at the University of Southern California

+ Multiple Sclerosis & Coronavirus

+ On the common cold

+ Information on Coronaviruses from the Institute for Animal Health

+ Coronaviridae database from International Committee on Taxonomy of Viruses (ICTV)

General sites on virology:

+ All the Virology on the WWW

+ General Virology from Science.org

+ Virology Resources


Fenner, Frank and David O. White, Medical Virology, San Diego: Academic Press, 1994, 451-455.

Levy, Jay A., Heinz Fraenkel-Conrat, and Robert A. Owens, Virology, Third Edition, Englewood Cliffs, New Jersey: Prentice Hall, 1994, 72-76.

Siddell, Stuart G., Ed., The Coronaviridae, New York: Plenum Press, 1995.


Created: February 1, 1999
Last modified: February 1, 1999