June 19, 2021

Coronaviruses | Molecular Biology of Coronaviruses | A Zoonotic Infection | Pathogenicity to Humans


Coronaviridae is a large family of RNA viruses which replicate by means of RNA dependent RNA polymerases. The Coronaviridae belongs to the order Nidovirales which infects amphibians, birds and mammals. They are highly pathogenic and therefore important human and veterinary pathogens worldwide. The Coronaviridae has been divided into two subfamilies- Orthocoronavirinae and letovirinae. The current classification recognizes 39 species in 26 subgenera, 5 genera and two subfamilies.

Taxonomy of Coronaviridae family with an indication of species known to be pathogenic to humans and cause respiratory diseases

The subfamily Orthocoronavirinae, whose members are typically referred to as coronaviruses is currently subdivided into four genera: Alpha, Beta, Delta and Gamma coronaviruses. The genus α-CoVs is the most taxonomically diversified and is represented by 17 identified species across 12 subgenera; Colacovirus, Decacovirus, Duvinacorvirus, Luchacovirus, Minacovirus, Minunacovirus, Myotacovirus, Nyctacovirus, Pedacovirus, Rhinacovirus, Setracovirus and Tegacovirus.

The β-CoVs are divided into 5 subgenera- Embecovirus, Hibecovirus, Merbecovirus, Nobecovirus, Sarbecovirus with a total of 12 species known so far. The  𝛿-CoVs and γ-CoVs are taxonomically divided into a respective 4 (Andecovirus, Buldecovirus, Herdecovirus, Moordecovirus), and two (Cegacovirus and Igacovirus) subgenera and contain a total of 7 and 2 species, respectively.


Bats and birds are ideal hosts for coronavirus gene source, bats for Alpha and Beta coronaviruses and birds for Delta and Gamma coronaviruses. Coronaviruses are usually associated with enteric and respiratory diseases in their hosts although hepatic, neurologic and other organ systems may be affected with certain coronaviruses. Lakes and rivers are an important habitat for bats and birds (including waterfowls) which are hosts for various coronavirus species and strains which shed viral particles in their feces. Besides the respiratory tract, coronaviruses pathogenic to humans can also infect the digestive system and be subsequently defecated. Considering this it is pivotal to understand whether aquatic environment and wastewater play a role in their dissemination particularly in areas with poor sanitation.


Molecular biology of coronaviruses

Their defining morphologic features are club-shaped projections, or crown like appearance (corona) from the virus envelope made up of highly glycosylated proteins named spike proteins. Coronavirus spike proteins are key determinants for virus attachment and entry into target cells. They are spherical, 50 – 200nm in diameter, enveloped positive single-stranded RNA viruses; the size of their genomes coiled inside a helical nucleocapsid of 9-11nm diameter ranges between 26.2 to 31.7kb (kilobases) making them the largest enveloped RNA viruses.

Electron micrograph and diagrammatic illustration of coronavirus

The first two-thirds of the genome consists of two large overlapping open reading frames that encode 16 non-structure proteins, including proteases, RNA-dependent RNA polymerase (prRdRp), RNA helicase, Primase and others that form the viral replicase complex, a platform to propagate viral mRNAs. These non-structural proteins are all potential targets for therapies. The remaining portion of the genome includes interspersed open reading frames for the structural proteins, as well as a number of accessory proteins.


A Zoonotic Infection

Transmissions from bats to intermediate hosts and then to humans, as well as from human to human, all involve viral adaptation, slight changes in viral sequence to improve fitness in new host. This is not unique to coronaviruses, as endemics and pandemics also occur when novel influenza A virus strain emerged in the human population from an animal host. Similar to introduction of Ebola virus and HIV-1 by mammals, many other viruses circulating in wild animals have the potential for zoonotic transmission.


There are over 60 coronaviruses that have been isolated from bats (Btcov) and most of these are in genus Betacoronavirus. Bats are large and highly mobile reservoirs of coronavirus. Bats have been implicated as a likely source of SARS-CoV2, as both SARS-CoV and MERS-CoV are genetically similar to viruses recovered from bats and bat coronaviruses can use human receptors for cell entry however, phylogenetic studies looking at sequence-based virus evolution suggests that the virus is not directly passed from bats to human but rather first infects intermediate animal hosts in close contact with humans. In the case of SARS-CoV these can be civets or raccoon dogs sold at crowded markets ;for MERS-CoV, they can be domesticated dromedary camels.


Pathogenicity to humans

Seven coronaviruses are known to cause disease in human. 4 of these HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1 most frequently cause common cold and rarely severe lower respiratory tract infection in infants, older people and the immunocompromised. The other 3 rarer forms (Beta coronaviruses) such as SARS (including the one causing Covid-19, SARS-CoV-2) and MERS-CoV cause much severe, sometimes fatal respiratory infection than other coronaviruses. The SARS-CoV and SARS-CoV-2 are two strains of the same species (Sarbecovirus subgenus) are the causative factors for Severe Acute Respiratory Syndrome (SARS and Covid-19 respectively) and MERS-CoV ( Merbicovirus subgenus) is the cause of Middle East Respiratory Syndrome (MERS). All of these strains have emerged from natural hosts and later spread through human to human transmission, predominately by droplet and contact routes. The fecal oral route is also plausible since, in case of some patients, the viral RNA was detected in fecal samples.


The outbreaks due to these highly pathogenic strains have revealed the potency and danger of this expanding family of pathogens that have the capacity to kill many thousands of people around the world. The mortality rate is disproportionately high in elderly and patients with preexisting co-morbidities such as heart disease, diabetes mellitus, hypertension and renal diseases. Higher morbidity in the elderly may partly be attributed to muted interferons antiviral responses as well as overall lower adaptive immunity.


SARS-CoV, MERS-CoV and SARS-CoV-2 are responsible for three major coronavirus-related outbreaks in humans within the past two decades. The SARS-CoV was responsible for the epidemic of SARS that originated in Guangdong Province in China in November 2002. Although the majority of cases were reported in China, the virus spread to 29 countries across Asia, North America, Europe and Oceania. Strict control measures were implemented to contain the outbreak. The last cases were reported in May 2004. A total of 8,096 confirmed cases were reported with a mortality rate of 9.6%. The first human cases of Middle East Respiratory Syndrome emerged in September 2012 in Saudi Arabia and a vast majority of nearly 2,500 confirmed cases have been associated with the Arabian Peninsula. However, as a result of travel, MERS-CoV was exported across the Middle East, Europe, North Africa, and Asia and reported by 27 countries to date. As of late 2019 the mortality rate was 34.4%. The most recent coronavirus-associated outbreak in humans emerged in late 2019 in the city of Wuhan, China and was caused by SARS-CoV-2. The Covid-19 outbreak cases exceeded 177 M according to WHO report as of 18th June, 2021 with a case fatality rate of 9.4%. The virus is still circulating despite all the precautionary and preventive measures. This has led to the development of over 300 vaccine projects. RNA viruses generally have high mutation rate. Genetic instability has long been considered to represent a challenge to develop effective vaccine against RNA viruses. Many vaccines have been developed. Mass vaccination is underway in many countries around the globe in a hope to control the pandemic.




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