The earliest reports of a coronavirus infection in animals occurred in the late 1920s, when an acute

respiratory infection of domesticated chickens emerged in North America. [15] 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%.[16] Leland David Bushnell and Carl Alfred Brandly
isolated the virus that caused the infection in 1933. [17] 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.[18] 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. [19] It was not realized at the time
that these three different viruses were related. [20][12]
Human coronaviruses were discovered in the 1960s [21][22] using two different methods in the United
Kingdom and the United States.[23] 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. [24][25][26] 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.[27] The new cultivating method was introduced to
the lab by Bertil Hoorn.[28] The isolated virus when intranasally inoculated into volunteers caused a
cold and was inactivated by ether which indicated it had a lipid envelope.[24][29] Dorothy Hamre[30] 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, designating it 229E. The novel virus
caused a cold in volunteers and, like B814, was inactivated by ether. [31]
Scottish virologist June Almeida at St Thomas' Hospital in London, collaborating with Tyrrell,
compared the structures of IBV, B814 and 229E in 1967. [32][33] Using electron microscopy the three
viruses were shown to be morphologically related by their general shape and distinctive club-
like spikes.[34] 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).[35] Like B814, 229E, and IBV, the novel cold virus OC43 had distinctive
club-like spikes when observed with the electron microscope. [36][37]
The IBV-like novel cold viruses were soon shown to be also morphologically related to the mouse
hepatitis virus.[19] This new group of viruses were named coronaviruses after their distinctive
morphological appearance.[7] Human coronavirus 229E and human coronavirus OC43 continued to
be studied in subsequent decades. [38][39] The coronavirus strain B814 was lost. It is not known which
present human coronavirus it was.[40] 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 2019.[41] There have also been a large number of animal coronaviruses identified
since the 1960s.[42]

Microbiology
Structure
Coronaviruses are large, roughly spherical particles with unique surface projections. [43] Their size is
highly variable with average diameters of 80 to 120 nm. Extreme sizes are known from 50 to 200 nm
in diameter.[44] The total molecular mass is on average 40,000 kDa. They are enclosed in an
envelope embedded with a number of protein molecules. [45] The lipid bilayer envelope, membrane
proteins, and nucleocapsid protect the virus when it is outside the host cell. [46]
The viral envelope is made up of a lipid bilayer in which the membrane (M), envelope (E)
and spike (S) structural proteins are anchored.[47] The molar ratio of E:S:M in the lipid bilayer is
approximately 1:20:300.[48] The E and M protein are the structural proteins that combined with the
lipid bilayer to shape the viral envelope and maintain its size. [49] S proteins are needed for interaction
with the host cells. But human coronavirus NL63 is peculiar in that its M protein has the binding site
for the host cell, and not its S protein.[50] The diameter of the envelope is 85 nm. 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). [51][49]
The M protein is the main structural protein of the envelope that provides the overall shape and is
a type III membrane protein. It consists of 218 to 263 Amino acid residues and forms a layer 7.8 nm
thick.[45] It has three domains, a short N-terminal ectodomain, a triple-spanning transmembrane
domain, and a C-terminal endodomain. The C-terminal domain forms a matrix-like lattice that adds
to the extra-thickness of the envelope. Different species can have either N- or O-linked glycans in
their protein amino-terminal domain. The M protein is crucial during the assembly, budding,
envelope formation, and pathogenesis stages of the virus lifecycle.[52]
The E proteins are minor structural proteins and highly variable in different species. [44] There are only
about 20 copies of the E protein molecule in a coronavirus particle. [48] They are 8.4 to 12 kDa in size
and are composed of 76 to 109 amino acids.[44] They are integral proteins (i.e. embedded in the lipid
layer) and have two domains namely a transmembrane domain and an extramembrane C-terminal
domain. They are almost fully α-helical, with a single α-helical transmembrane domain, and form
pentameric (five-molecular) ion channels in the lipid bilayer. They are responsible for virion
assembly, intracellular trafficking and morphogenesis (budding). [45]
The spikes are the most distinguishing feature of coronaviruses and are responsible for the corona-
or halo-like surface. On average a coronavirus particle has 74 surface spikes. [53] Each spike is about
20 nm long and is composed of a trimer of the S protein. The S protein is in turn 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 two subunits remain
noncovalently linked as they are exposed on the viral surface until they attach to the host cell
membrane.[45] In a functionally active state, three S1 are attached to two S2 subunits. The subunit
complex is split into individual subunits when the virus binds and fuses with the host cell under the
action of proteases such as cathepsin family and transmembrane protease serine 2 (TMPRSS2) of
the host cell.[54]
S1 proteins are the most critical components in terms of infection. They are also the most variable
components as they are responsible for host cell specificity. They possess two major domains
named N-terminal domain (S1-NTD) and C-terminal domain (S1-CTD), both of which serve as the
receptor-binding domains. The NTDs recognize and bind sugars on the surface of the host cell. An
exception is the MHV NTD that binds to a protein receptor carcinoembryonic antigen-related cell
adhesion molecule 1 (CEACAM1). S1-CTDs are responsible for recognizing different protein
receptors such as angiotensin-converting enzyme 2 (ACE2), aminopeptidase N (APN),
and dipeptidyl peptidase 4 (DPP4).[45]
A subset of coronaviruses (specifically the members of betacoronavirus subgroup A) also has a
shorter spike-like surface protein called hemagglutinin esterase (HE).[42] The HE proteins occur as
homodimers composed of about 400 amino acid residues and are 40 to 50 kDa in size. They appear
as tiny surface projections of 5 to 7 nm long embedded in between the spikes. They help in the
attachment to and detachment from the host cell.[55]
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. [49][56] N protein is a phosphoprotein of 43 to 50 kDa
in size, and is divided into three conserved domains. SOURCE: WIKI