Illustration of the morphology of corona viruses; the club-shaped viral spike peplomers, colored red, create the look of a corona surrounding the virion when observed with an electron microscope.
Transmission electron micrograph (TEM) of avian infectious bronchitis virus
Transmission electron micrograph of infectious bronchitis viruses
Corona viruses are a group of related RNA viruses that cause diseases in mammals and birds.
In humans, these viruses cause respiratory tract infections that can range from mild to lethal. Mild illnesses include some cases of the common cold (which is caused also by certain other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARS, MERS, and COVID-19. Symptoms in other species vary: in chickens, they cause an upper respiratory tract disease, while in cows and pigs they cause diarrhea.
There are as yet no vaccines or antiviral drugs to prevent or treat human coronavirus infections.
Corona viruses constitute the subfamily Ortho corona virinae, in the family Corona viridae, order Nidovirales, and realm Riboviria. They are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid of helical symmetry.
This is wrapped in a icosahedral protein shell. The genome size of coronaviruses ranges from approximately 26 to 32 kilobases, one of the largest among RNA viruses.
They have characteristic club-shaped spikes that project from their surface, which in electron micrographs create an image reminiscent of the solar corona, from which their name derives.
The name “corona virus” is derived from Latin corona, meaning “crown” or “wreath”, itself a borrowing from Greek κορώνη korṓnē, “garland, wreath”.
The name was coined by June Almeida and David Tyrrell who first observed and studied human corona viruses.
The word was first used in print in 1968 by an informal group of virologists in the journal Nature to designate the new family of viruses.
The name refers to the characteristic appearance of virions (the infective form of the virus) by electron microscopy, which have a fringe of large, bulbous surface projections creating an image reminiscent of the solar corona or halo.
This morphology is created by the viral spike peplomers, which are proteins on the surface of the virus.
Transmission electron micrograph of organ cultured coronavirus OC43
Corona viruses were first discovered in the 1930s when an acute respiratory infection of domesticated chickens was shown to be caused by infectious bronchitis virus (IBV).
Arthur Schalk and M.C. Hawn described in 1931 a new respiratory infection of chickens in North Dakota. The infection of new-born chicks was characterized by gasping and listlessness.
The mortality rate of the chicks was 40–90%. Fred Beaudette and Charles Hudson six years later successfully isolated and cultivated the infectious bronchitis virus which caused the disease.
In the 1940s, two more animal corona viruses, mouse hepatitis virus (MHV) and transmissible gastroenteritis virus (TGEV), were isolated.
It was not realized at the time that these three different viruses were related.
Human corona viruses were discovered in the 1960s.
They were isolated using two different methods in the United Kingdom and the United States.
E.C. Kendall, Malcom Byone, and David Tyrrell working at the Common Cold Unit of the British Medical Research Council in 1960 isolated from a boy a novel common cold virus B814.
The virus was not able to be cultivated using standard techniques which had successfully cultivated rhino viruses, adeno viruses and other known common cold viruses.
In 1965, Tyrrell and Byone successfully cultivated the novel virus by serially passing it through organ culture of human embryonic trachea.
The new cultivating method was introduced to the lab by Bertil Hoorn.
The isolated virus when intranasally inoculated into volunteers caused a cold and was inactivated by ether which indicated it had a lipid envelope.
Around the same time, Dorothy Hamre and John Procknow at the University of Chicago isolated a novel cold virus 229E from medical students, which they grew in kidney tissue culture.
The novel virus 229E, like the virus strain B814, when inoculated into volunteers caused a cold and was inactivated by ether.
The two novel strains B814 and 229E were subsequently imaged by electron microscopy in 1967 by Scottish virologist June Almeida at St. Thomas Hospital in London.
Almeida through electron microscopy was able to show that B814 and 229E were morphologically related by their distinctive club-like spikes.
Not only were they related with each other, but they were morphologically related to infectious bronchitis virus (IBV).
A research group at the National Institute of Health the same year was able to isolate another member of this new group of viruses using organ culture and named the virus strain OC43 (OC for organ culture).
Like B814, 229E, and IBV, the novel cold virus OC43 had distinctive club-like spikes when observed with the electron microscope.
The IBV-like novel cold viruses were soon shown to be also morphologically related to the mouse hepatitis virus.
This new group of IBV-like viruses came to be known as corona viruses after their distinctive morphological appearance.
Human corona virus 229E and human corona virus OC43 continued to be studied in subsequent decades.
The corona virus strain B814 was lost.
It is not known which present human corona virus it was.
Other human corona viruses have since been identified, including SARS-CoV in 2003, HCoV NL63 in 2004, HCoV HKU1 in 2005, MERS-CoV in 2012, and SARS-CoV-2 in 2019.
There have also been a large number of animal coronaviruses identified since the 1960s.
Cross-sectional model of a coronavirus
Corona viruses are large, mostly spherical, sometimes pleomorphic (changeable in shape), particles with bulbous surface projections.
The average diameter of the virus particles is around 125 nm (.125 μm).
The diameter of the envelope is 85 nm and the spikes are 20 nm long.
The envelope of the virus in electron micrographs appears as a distinct pair of electron-dense shells (shells that are relatively opaque to the electron beam used to scan the virus particle).
The viral envelope consists of a lipid bilayer, in which the membrane (M), envelope (E) and spike (S) structural proteins are anchored.
The ratio of E:S:M in the lipid bilayer is approximately 1:20:300. On average a corona virus particle has 74 surface spikes.
A subset of corona viruses (specifically the members of beta corona virus subgroup A) also have a shorter spike-like surface protein called hemagglutinin esterase (HE).
The corona virus surface spikes are homotrimers of the S protein, which is composed of an S1 and S2 subunit.
The homotrimeric S protein is a class I fusion protein which mediates the receptor binding and membrane fusion between the virus and host cell.
The S1 subunit forms the head of the spike and has the receptor binding domain (RBD).
The S2 subunit forms the stem which anchors the spike in the viral envelope and on protease activation enables fusion.
The E and M protein are important in forming the viral envelope and maintaining its structural shape.
Inside the envelope, there is the nucleocapsid, which is formed from multiple copies of the nucleocapsid (N) protein, which are bound to the positive-sense single-stranded RNA genome in a continuous beads-on-a-string type conformation.
The lipid bilayer envelope, membrane proteins, and nucleocapsid protect the virus when it is outside the host cell.
Schematic representation of the genome organization and functional domains of S protein for SARS-CoV and MERS-CoV
Corona viruses contain a positive-sense, single-stranded RNA genome.
The genome size for corona viruses ranges from 26.4 to 31.7 kilo bases.
The genome size is one of the largest among RNA viruses. The genome has a 5′ methylated cap and a 3′ polyadenylated tail.
The genome organization for a coronavirus is 5′-leader-UTR-replicase/transcriptase-spike (S)-envelope (E)-membrane (M)-nucleocapsid (N)-3′UTR-poly (A) tail.
The open reading frames 1a and 1b, which occupy the first two-thirds of the genome, encode the replicase/transcriptase polyprotein.
The replicase/transcriptase polyprotein self cleaves to form nonstructural proteins.
The later reading frames encode the four major structural proteins: spike, envelope, membrane, and nucleocapsid. Interspersed between these reading frames are the reading frames for the accessory proteins.
The number of accessory proteins and their function is unique depending on the specific corona virus.
The life cycle of a corona virus
Infection begins when the viral spike (S) glycoprotein attaches to its complementary host cell receptor.
After attachment, a protease of the host cell cleaves and activates the receptor-attached spike protein.
Depending on the host cell protease available, cleavage and activation allows the virus to enter the host cell by endocytosis or direct fusion of the viral envelop with the host membrane.
On entry into the host cell, the virus particle is uncoated, and its genome enters the cell cytoplasm.
The corona virus RNA genome has a 5′ methylated cap and a 3′ polyadenylated tail, which allows the RNA to attach to the host cell’s ribosome for translation.
The host ribosome translates the initial overlapping open reading frame of the virus genome and forms a long polyprotein.
The polyprotein has its own proteases which cleave the polyprotein into multiple nonstructural proteins.
A number of the nonstructural proteins coalesce to form a multi-protein replicase-transcriptase complex (RTC).
The main replicase-transcriptase protein is the RNA-dependent RNA polymerase (RdRp). It is directly involved in the replication and transcription of RNA from an RNA strand.
The other nonstructural proteins in the complex assist in the replication and transcription process.
The exoribonuclease nonstructural protein, for instance, provides extra fidelity to replication by providing a proofreading function which the RNA-dependent RNA polymerase lacks.
One of the main functions of the complex is to replicate the viral genome.
RdRp directly mediates the synthesis of negative-sense genomic RNA from the positive-sense genomic RNA.
This is followed by the replication of positive-sense genomic RNA from the negative-sense genomic RNA. The other important function of the complex is to transcribe the viral genome.
RdRp directly mediates the synthesis of negative-sense subgenomic RNA molecules from the positive-sense genomic RNA.
This is followed by the transcription of these negative-sense subgenomic RNA molecules to their corresponding positive-sense mRNAs.
The replicated positive-sense genomic RNA becomes the genome of the progeny viruses.
The mRNAs are gene transcripts of the last third of the virus genome after the initial overlapping reading frame.
These mRNAs are translated by the host’s ribosomes into the structural proteins and a number of accessory proteins.
RNA translation occurs inside the endoplasmic reticulum.
The viral structural proteins S, E, and M move along the secretory pathway into the Golgi intermediate compartment.
There, the M proteins direct most protein-protein interactions required for assembly of viruses following its binding to the nucleocapsid.
Progeny viruses are then released from the host cell by exocytosis through secretory vesicles.
Infected carriers are able to shed viruses into the environment.
The interaction of the corona virus spike protein with its complementary cell receptor is central in determining the tissue tropism, infectivity, and species range of the released virus.
Corona viruses mainly target epithelial cells. They are transmitted from one host to another host, depending on the corona virus species, by either an aerosol, fomite, or fecal-oral route.
Human corona viruses infect the epithelial cells of the respiratory tract, while animal corona viruses generally infect the epithelial cells of the digestive tract.
SARS corona virus, for example, infects via an aerosol route, the human epithelial cells of the lungs by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.
Transmissible gastroenteritis corona virus (TGEV) infects, via a fecal-oral route, the pig epithelial cells of the digestive tract by binding to the alanine aminopeptidase (APN) receptor.
Phylogenetic tree of corona viruses
The scientific name for corona virus is Ortho corona virinae or Corona virinae.
Corona viruses belong to the family of Corona viridae, order Nidovirales, and realm Riboviria.
They are divided into alpha corona viruses and beta corona viruses which infect mammals – and gamma corona viruses and delta corona viruses which primarily infect birds.
- Genus: Alpha corona virus; type species: Alpha corona virus 1 (TGEV)
- Species: Alpha corona virus 1, Human corona virus 229E, Human corona virus NL63, Miniopterus bat corona virus 1, Miniopterus bat corona virus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat corona virus HKU2, Scotophilus bat corona virus 512
- Genus Beta corona virus; type species: Murine corona virus (MHV)
- Species: Betacoronavirus 1 (Bovine Corona virus, Human coronavirus OC43), Hedgehog corona virus 1, Human corona virus HKU1, Middle East respiratory syndrome-related corona virus, Murine corona virus, Pipistrellus bat corona virus HKU5, Rousettus bat corona virus HKU9, Severe acute respiratory syndrome-related corona virus (SARS-CoV, SARS-CoV-2), Tylonycteris bat corona virus HKU4
- Genus Gamma corona virus; type species: Avian corona virus (IBV)
- Species: Avian corona virus, Beluga whale corona virus SW1
- Genus Delta corona virus; type species: Bulbul corona virus HKU11
- Species: Bulbul corona virus HKU11, Porcine corona virus HKU15
Origins of human corona viruses with possible intermediate hosts
The most recent common ancestor (MRCA) of all corona viruses is estimated to have existed as recently as 8000 BCE, although some models place the common ancestor as far back as 55 million years or more, implying long term coevolution with bat and avian species.
The most recent common ancestor of the alpha corona virus line has been placed at about 2400 BCE, the beta corona virus line at 3300 BCE, the gamma corona virus line at 2800 BCE, and the delta corona virus line at about 3000 BCE. Bats and birds, as warm-blooded flying vertebrates, are an ideal natural reservoir for the corona virus gene pool (bats the reservoir for alpha corona virus and beta corona virus – and birds the reservoir for gamma corona virus and delta corona virus). The large number of host bat and avian species, and their global range, has enabled extensive evolution and dissemination of corona viruses.
Many human corona virus have their origin in bats.
The human corona virus NL63 shared a common ancestor with a bat corona virus (ARCoV.2) between 1190–1449 CE. The human corona virus 229E shared a common ancestor with bat corona virus (GhanaGrp1 Bt CoV) between 1686–1800 CE. More recently, alpaca corona virus and human corona virus 229E diverged sometime before 1960.
MERS-CoV emerged in humans from bats through the intermediate host of camels.
MERS-CoV, although related to several bat corona virus species, appears to have diverged from these several centuries ago.
The most closely related bat corona virus and SARS-CoV diverged in 1986.
A possible path of evolution, of SARS corona virus and keen bat corona viruses, suggests that SARS related corona viruses coevolved in bats for a long time.
The ancestors of SARS-CoV first infected leaf-nose bats of the genus Hipposideridae; subsequently, they spread to horseshoe bats in the species Rhinolophidae, and then to civets, and finally to humans.
Unlike other beta corona viruses, bovine corona virus of the species Beta corona virus 1 and subgenus Embecovirus is thought to have originated in rodents and not in bats.
In the 1790s, equine corona virus diverged from the bovine corona virus after a cross-species jump.
Later in the 1890s, human corona virus OC43 diverged from bovine corona virus after another cross-species spillover event.
It is speculated that the flu pandemic of 1890 may have been caused by this spillover event, and not by the influenza virus, because of the related timing, neurological symptoms, and unknown causative agent of the pandemic.
Human corona virus OC43 besides causing respiratory infections is also suspected of playing a role in neurological diseases.
In the 1950s, the human corona virus OC43 began to diverge into its present genotypes. Phylogentically, mouse hepatitis virus (Murine corona virus), which infects the mouse’s liver and the central nervous system, is related to human corona virus OC43 and bovine corona virus. Human corona virus HKU1, like the aforementioned viruses, also has its origins in rodents.
Infection in humans
Illustration of SARSr-CoV virion
Seasonal distribution of HCoV-NL63 in Germany shows a preferential detection from November to March
Corona viruses vary significantly in risk factor.
Some can kill more than 30% of those infected, such as MERS-CoV, and some are relatively harmless, such as the common cold.
Corona viruses can cause colds with major symptoms, such as fever, and a sore throat from swollen adenoids.
Corona viruses can cause pneumonia (either direct viral pneumonia or secondary bacterial pneumonia) and bronchitis (either direct viral bronchitis or secondary bacterial bronchitis).
The human corona virus discovered in 2003, SARS-CoV, which causes severe acute respiratory syndrome (SARS), has a unique pathogenesis because it causes both upper and lower respiratory tract infections.
Six species of human corona viruses are known, with one species subdivided into two different strains, making seven strains of human corona viruses altogether.
Four of these corona viruses continually circulate in the human population and produce the generally mild symptoms of the common cold in adults and children worldwide: -OC43, -HKU1, HCoV-229E, -NL63.
These corona viruses cause about 15% of common colds, while 40 to 50% of colds are caused by rhino viruses.
The four mild corona viruses have a seasonal incidence occurring in the winter months in temperate climates.
There is no preference towards a particular season in tropical climates.
Four human corona viruses produce symptoms that are generally mild:
- Human corona virus OC43 (HCoV-OC43), β-CoV
- Human corona virus HKU1 (HCoV-HKU1), β-CoV
- Human corona virus 229E (HCoV-229E), α-CoV
- Human corona virus NL63 (HCoV-NL63), α-CoV
Three human coronaviruses produce symptoms that are potentially severe:
- Middle East respiratory syndrome-related corona virus (MERS-CoV), β-CoV
- Severe acute respiratory syndrome corona virus (SARS-CoV), β-CoV
- Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), β-CoV
Severe acute respiratory syndrome (SARS)
In 2003, following the outbreak of severe acute respiratory syndrome (SARS) which had begun the prior year in Asia, and secondary cases elsewhere in the world, the World Health Organization (WHO) issued a press release stating that a novel corona virus identified by a number of laboratories was the causative agent for SARS.
The virus was officially named the SARS corona virus (SARS-CoV). More than 8,000 people were infected, about ten percent of whom died.
Middle East respiratory syndrome (MERS)
In September 2012, a new type of corona virus was identified, initially called Novel Corona virus 2012, and now officially named Middle East respiratory syndrome corona virus (MERS-CoV).
The World Health Organization issued a global alert soon after.
The WHO update on 28 September 2012 said the virus did not seem to pass easily from person to person.
However, on 12 May 2013, a case of human-to-human transmission in France was confirmed by the French Ministry of Social Affairs and Health. In addition, cases of human-to-human transmission were reported by the Ministry of Health in Tunisia.
Two confirmed cases involved people who seemed to have caught the disease from their late father, who became ill after a visit to Qatar and Saudi Arabia.
Despite this, it appears the virus had trouble spreading from human to human, as most individuals who are infected do not transmit the virus.
By 30 October 2013, there were 124 cases and 52 deaths in Saudi Arabia.
After the Dutch Erasmus Medical Centre sequenced the virus, the virus was given a new name, Human Corona virus—Erasmus Medical Centre (HCoV-EMC).
The final name for the virus is Middle East respiratory syndrome corona virus (MERS-CoV).
The only U.S. cases (both survived) were recorded in May 2014.
In May 2015, an outbreak of MERS-CoV occurred in the Republic of Korea, when a man who had traveled to the Middle East, visited four hospitals in the Seoul area to treat his illness.
This caused one of the largest outbreaks of MERS-CoV outside the Middle East.
As of December 2019, 2,468 cases of MERS-CoV infection had been confirmed by laboratory tests, 851 of which were fatal, a mortality rate of approximately 34.5%.
In December 2019, a pneumonia outbreak was reported in Wuhan, China. On 31 December 2019, the outbreak was traced to a novel strain of coronavirus, which was given the interim name 2019-nCoV by the World Health Organization (WHO), later renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses.
As of 2 May 2020, there have been at least 238,775 confirmed deaths and more than 3,344,274 confirmed cases in the corona virus pneumonia pandemic.
The Wuhan strain has been identified as a new strain of Beta corona virus from group 2B with approximately 70% genetic similarity to the SARS-CoV.
The virus has a 96% similarity to a bat corona virus, so it is widely suspected to originate from bats as well.
The pandemic has resulted in travel restrictions and nationwide lockdowns in several countries.
Infection in other animals
Corona viruses have been recognized as causing pathological conditions in veterinary medicine since the 1930s.
Except for avian infectious bronchitis, the major related diseases have mainly an intestinal location.
Corona viruses primarily infect the upper respiratory and gastrointestinal tract of mammals and birds.
They also cause a range of diseases in farm animals and domesticated pets, some of which can be serious and are a threat to the farming industry.
In chickens, the infectious bronchitis virus (IBV), a corona virus, targets not only the respiratory tract but also the urogenital tract.
The virus can spread to different organs throughout the chicken.
Economically significant corona viruses of farm animals include porcine corona virus (transmissible gastroenteritis corona virus, TGE) and bovine corona virus, which both result in diarrhea in young animals.
Feline corona virus: two forms, feline enteric corona virus is a pathogen of minor clinical significance, but spontaneous mutation of this virus can result in feline infectious peritonitis (FIP), a disease associated with high mortality.
Similarly, there are two types of corona virus that infect ferrets: Ferret enteric corona virus causes a gastrointestinal syndrome known as epizootic catarrhal enteritis (ECE), and a more lethal systemic version of the virus (like FIP in cats) known as ferret systemic corona virus (FSC).
There are two types of canine corona virus (CCoV), one that causes mild gastrointestinal disease and one that has been found to cause respiratory disease.
Mouse hepatitis virus (MHV) is a corona virus that causes an epidemic murine illness with high mortality, especially among colonies of laboratory mice.
Sialodacryoadenitis virus (SDAV) is highly infectious corona virus of laboratory rats, which can be transmitted between individuals by direct contact and indirectly by aerosol.
Acute infections have high morbidity and tropism for the salivary, lachrymal and harderian glands.
A HKU2-related bat corona virus called swine acute diarrhea syndrome corona virus (SADS-CoV) causes diarrhea in pigs.
Prior to the discovery of SARS-CoV, MHV had been the best-studied corona virus both in vivo and in vitro as well as at the molecular level.
Some strains of MHV cause a progressive demyelinating encephalitis in mice which has been used as a murine model for multiple sclerosis.
Significant research efforts have been focused on elucidating the viral pathogenesis of these animal corona viruses, especially by virologists interested in veterinary and zoonotic diseases.
- Infectious bronchitis virus (IBV) causes avian infectious bronchitis.
- Porcine corona virus (transmissible gastroenteritis corona virus of pigs, TGEV).
- Bovine corona virus (BCV), responsible for severe profuse enteritis in of young calves.
- Feline corona virus (FCoV) causes mild enteritis in cats as well as severe Feline infectious peritonitis (other variants of the same virus).
- the two types of canine corona virus (CCoV) (one causing enteritis, the other found in respiratory diseases).
- Turkey corona virus (TCV) causes enteritis in turkeys.
- Ferret enteric corona virus causes epizootic catarrhal enteritis in ferrets.
- Ferret systemic corona virus causes FIP-like systemic syndrome in ferrets.
- Pantropic canine corona virus.
- Rabbit enteric corona virus causes acute gastrointestinal disease and diarrhea in young European rabbits. Mortality rates are high.
- Porcine epidemic diarrhea virus (PED or PEDV), has emerged around the world.