Michelle Hsiang's
Coronaviridae Webpage
Introduction
Issues of Classification
Timeline
Historical Notes
Unique Replication
Recent Updates
Useful web links
References
+, 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
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 |
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.
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
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.
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
Information on Coronaviruses from the Institute for Animal
Health
Coronaviridae database
from International Committee on Taxonomy of Viruses (ICTV)
General sites on virology:
General Virology
from Science.org
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.