Corona Virus

Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold (which is also caused by other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARSMERS, and COVID-19. In cows and pigs they cause diarrhea, while in mice they cause hepatitis and encephalomyelitis. There are as yet no vaccines or antiviral drugs to prevent or treat human coronavirus infections.Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold (which is also caused by other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARSMERS, and COVID-19. In cows and pigs they cause diarrhea, while in mice they cause hepatitis and encephalomyelitis. There are as yet no vaccines or antiviral drugs to prevent or treat human coronavirus infections.

Illustration of a SARS-CoV-2 virion :-  1.Red protrusions: spikeproteins (S)   2.Grey coating: lipid bilayerenvelope . 3.Yellow deposits: envelope proteins(E)  .  4.  Orange deposits: membrane proteins (M)

Virus Classification :- (unranked):Virus Realm:Riboviria Kingdom:Orthornavirae Phylum:Pisuviricota Class:Pisoniviricetes Order:Nidovirales Family:Coronaviridae Subfamily:Orthocoronavirinae

Etymology:- The name “coronavirus” 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 coronaviruses.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.

The earliest reports of an illness caused by a coronavirus occurred in the late 1920s, when an acute respiratory infection of domesticated chickens emerged in North America.Arthur Schalk and M.C. Hawn in 1931 made the first detailed report which described a new respiratory infection of chickens in North Dakota. The infection of new-born chicks was characterized by gasping and listlessness with high mortality rates of 40–90%.Leland David Bushnell and Carl Alfred Brandly isolated the virus in 1933.The virus was then known as infectious bronchitis virus (IBV). Charles D. Hudson and Fred Robert Beaudette cultivated the virus for the first time in 1937.The specimen came to be known as the Beaudette strain. In the late 1940s, two more animal coronaviruses, JHM that causes brain disease (murine encephalitis) and mouse hepatitis virus (MHV) that causes hepatitis in mice were discovered. It was not realized at the time that these three different viruses were related.

Human coronaviruses were discovered in the 1960susing two different methods in the United Kingdom and the United States.E.C. Kendall, Malcolm Bynoe, and David Tyrrell working at the Common Cold Unit of the British Medical Research Council collected a unique common cold virus designated B814 in 1961.The virus could not be cultivated using standard techniques which had successfully cultivated rhinoviruses, adenoviruses and other known common cold viruses. In 1965, Tyrrell and Bynoe 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.Dorothy Hamre and John Procknow at the University of Chicago isolated a novel cold from medical students in 1962. They isolated and grew the virus in kidney tissue culture, assigning it as 229E. The novel virus caused a cold in volunteers and was inactivated by ether similarly as B814.Scottish virologist June Almeida at St. Thomas Hospital in London, collaborating with Tyrrell, compared the structures of IBV, B814 and 229E in 1967.

Using electron microscopy the three viruses were shown to be morphologically related by their general shape and distinctive club-like spikes.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 one of the samples 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 viruses were named coronaviruses after their distinctive morphological appearance.Human coronavirus 229E and human coronavirus OC43 continued to be studied in subsequent decade.The coronavirus strain B814 was lost. It is not known which present human coronavirus it was.Other human coronaviruses have since been identified, including SARS-CoV in 2003, HCoV NL63 in 2003, HCoV HKU1 in 2004, MERS-CoV in 2013, and SARS-CoV-2 in 2020.There have also been a large number of animal coronaviruses identified since the 1960s.

Microbiology :- Coronaviruses are large, roughly spherical 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.[47] The ratio of E:S:M in the lipid bilayer is approximately 1:20:300.On average a coronavirus particle has 74 surface spikes.A subset of coronaviruses (specifically the members of betacoronavirus subgroup A) also have a shorter spike-like surface protein called hemagglutinin esterase (HE).

The coronavirus 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.

Genome
See also: Severe acute respiratory syndrome-related coronavirus § Genome

Schematic representation of the genome organization and functional domains of S protein for SARS-CoV and MERS-CoV
Coronaviruses contain a positive-sense, single-stranded RNA genome. The genome size for coronaviruses ranges from 26.4 to 31.7 kilobases.[9] 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 (ORF1ab)-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 polyprotein (pp1ab). The replicase polyprotein self cleaves to form 16 nonstructural proteins (nsp1–nsp16).

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 coronavirus.

Replication cycle
Cell entry

The life cycle of a coronavirus
Infection begins when the viral spike protein 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.
Genome translation
On entry into the host cell, the virus particle is uncoated, and its genome enters the cell cytoplasm. The coronavirus RNA genome has a 5′ methylated cap and a 3′ polyadenylated tail, which allows it to act like a messenger RNA and be directly translated by the host cell’s ribosomes. The host ribosomes translate the initial overlapping open reading frames ORF1a and ORF1b of the virus genome into two large overlapping polyproteins, pp1a and pp1ab.
SARS-CoV genome and proteins
The larger polyprotein pp1ab is a result of a -1 ribosomal frameshift caused by a slippery sequence (UUUAAAC) and a downstream RNA pseudoknot at the end of open reading frame ORF1a.The ribosomal frameshift allows for the continuous translation of ORF1a followed by ORF1b.

The polyproteins have their own proteases, PLpro (nsp3) and 3CLpro (nsp5), which cleave the polyproteins at different specific sites. The cleavage of polyprotein pp1ab yields 16 nonstructural proteins (nsp1 to nsp16). Product proteins include various replication proteins such as RNA-dependent RNA polymerase (nsp12), RNA helicase (nsp13), and exoribonuclease (nsp14).

Replicase-transcriptase

Replicase-transcriptase complex
A number of the nonstructural proteins coalesce to form a multi-protein replicase-transcriptase complex. 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.

Replication – 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.


Transcription of nested mRNAs

Nested set of subgenomic mRNAs
Transcription – 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 process is followed by the transcription of these negative-sense subgenomic RNA molecules to their corresponding positive-sense mRNAs.The subgenomic mRNAs form a “nested set” which have a common 5′-head and partially duplicate 3′-end.
Recombination – The replicase-transcriptase complex is also capable of genetic recombination when at least two viral genomes are present in the same infected cell.RNA recombination appears to be a major driving force in determining genetic variability within a coronavirus species, the capability of a coronavirus species to jump from one host to another and, infrequently, in determining the emergence of novel coronaviruses.The exact mechanism of recombination in coronaviruses is unclear, but likely involves template switching during genome replication.
Assembly and release
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. Once released the viruses can infect other host cells.
Transmission
Infected carriers are able to shed viruses into the environment. The interaction of the coronavirus spike protein with its complementary cell receptor is central in determining the tissue tropism, infectivity, and species range of the released virus.Coronaviruses mainly target epithelial cells.They are transmitted from one host to another host, depending on the coronavirus species, by either an aerosol, fomite, or fecal-oral route.
Human coronaviruses infect the epithelial cells of the respiratory tract, while animal coronaviruses generally infect the epithelial cells of the digestive tract.SARS coronavirus, 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 coronavirus (TGEV) infects, via a fecal-oral route,the pig epithelial cells of the digestive tract by binding to the alanine aminopeptidase (APN) receptor.

Classification :- The scientific name for coronavirus is Orthocoronavirinae or Coronavirinae.

Coronaviruses belong to the family of Coronaviridae, order Nidovirales, and realm Riboviria.They are divided into alphacoronaviruses and betacoronaviruses which infect mammals – and gammacoronaviruses and deltacoronaviruses, which primarily infect birds.

Genus: Alphacoronavirus;type species: Alphacoronavirus 1 (TGEV)
Species: Alphacoronavirus 1, Human coronavirus 229E, Human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2, Scotophilus bat coronavirus 512
Genus Betacoronavirus;type species: Murine coronavirus (MHV)
Species: Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Hedgehog coronavirus 1, Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Severe acute respiratory syndrome-related coronavirus (SARS-CoV, SARS-CoV-2), Tylonycteris bat coronavirus HKU4
Genus Gammacoronavirus;type species: Avian coronavirus (IBV)
Species: Avian coronavirus, Beluga whale coronavirus SW1
Genus Deltacoronavirus; type species: Bulbul coronavirus HKU11
Species: Bulbul coronavirus HKU11, Porcine coronavirus HKU15.

Origin :- The most recent common ancestor (MRCA) of all coronaviruses 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 alphacoronavirus line has been placed at about 2400 BCE, of the betacoronavirus line at 3300 BCE, of the gammacoronavirus line at 2800 BCE, and of the deltacoronavirus line at about 3000 BCE. Bats and birds, as warm-blooded flying vertebrates, are an ideal natural reservoir for the coronavirus gene pool (with bats the reservoir for alphacoronaviruses and betacoronavirus – and birds the reservoir for gammacoronaviruses and deltacoronaviruses). The large number and global range of bat and avian species that host viruses has enabled extensive evolution and dissemination of coronaviruses.

Many human coronaviruses have their origin in bats.The human coronavirus NL63 shared a common ancestor with a bat coronavirus (ARCoV.2) between 1190 and 1449 CE.The human coronavirus 229E shared a common ancestor with a bat coronavirus (GhanaGrp1 Bt CoV) between 1686 and 1800 CE.More recently, alpaca coronavirus and human coronavirus 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 coronavirus species, appears to have diverged from these several centuries ago.The most closely related bat coronavirus and SARS-CoV diverged in 1986.A possible path of evolution of SARS coronavirus and keen bat coronaviruses is that SARS-related coronaviruses 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, then to Asian palm civets, and finally to humans.
Unlike other betacoronaviruses, bovine coronavirus of the species Betacoronavirus 1 and subgenus Embecovirus is thought to have originated in rodents and not in bats. In the 1790s, equine coronavirus diverged from the bovine coronavirus after a cross-species jump.Later in the 1890s, human coronavirus OC43 diverged from bovine coronavirus 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.Besides causing respiratory infections, human coronavirus OC43 is also suspected of playing a role in neurological diseases.In the 1950s, the human coronavirus OC43 began to diverge into its present genotypes.Phylogentically, mouse hepatitis virus (Murine coronavirus), which infects the mouse’s liver and central nervous system is related to human coronavirus OC43 and bovine coronavirus. Human coronavirus HKU1, like the aforementioned viruses, also has its origins in rodents.

Prevention and treatment:- There are no vaccines or antiviral drugs to prevent or treat human coronavirus infections. Treatment is only supportive. A number of antiviral targets have been identified such as viral proteases, polymerases, and entry proteins. Drugs are in development which target these proteins and the different steps of viral replication. A number of vaccines using different methods are also under development for different human coronaviruses.

There are no antiviral drugs to treat animal coronaviruses.[citation needed] Vaccines are available for IBV, TGEV, and Canine CoV, although their effectiveness is limited. In the case of outbreaks of highly contagious animal coronaviruses, such as PEDV, measures such as destruction of entire herds of pigs may be used to prevent transmission to other herds.

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