What are coronaviruses?

15 April 2020

CORONAVIRUS

Coronavirus particles

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The members of the coronavirus family are widespread in nature, infecting humans, mammals and birds...

Like all viruses, coronaviruses are much smaller than bacteria and can only be visualized using a powerful electron microscope. Each virus particle is about 1/10,000th of a millimetre across and resembles a “spiky football”. The spikes - or surface glycoproteins - that protrude from the surfaces of the viral particles play a crucial role in binding to cells targeted by the virus for infection. 

The spikes are embedded in an oily layer called the viral envelope. Once a virus particle meets a susceptible cell in the body, which is usually in the respiratory tract in the case of the human coronaviruses, the spikes lock on to structures on the cell surfaces called “receptors”. This brings together the virus envelope and the cell membrane, and the two fuse together in a process similar to two soap bubbles merging.

When this occurs, the contents of the virus particle are released into the cell. This includes the viral genetic material, which encodes the instructions for hijacking the cell and transforming it into a production line for new coronaviruses. Each infected cell subsequently churns out hundreds of new viral particles before the demands of supporting reproduction of the virus overwhelm it and the cell dies. In some cases, the immune system detects the infection and destroys the cell to halt viral production.

The genetic material of coronaviruses is a chemical relative of DNA called RNA. Unlike its double-stranded DNA cousin, RNA consists of a single chain of between 26,000 and 32,000 genetic letters.  This is twice the length of the influenza virus genome and four times the size of polio virus. Consequently, as a group, coronaviruses have the largest genomes among the RNA viruses.

Once the coronavirus RNA gets inside the cell, the cell is tricked into regarding the viral RNA as a normal cellular “messenger RNA” used to make proteins. Structures in the cell called ribosomes read the viral genetic message and translate it into two long viral proteins. These are called “polyproteins” because they consist of number of separate smaller proteins linked together like a string of sausages.

Protein-cutting enzymes encoded by the virus chop up these long polyproteins into their separate protein “sausages”, which then organise themselves into a three-dimensional structure called the replicase transcription complex, which coordinates the subsequent reproduction of new viruses in the cell.

One of the roles of the replicase transcription complex is to copy the original viral RNA to produce a stock of new viral RNA genomes for packaging inside freshly-assembled viral particles. It also produces shorter – so called “subgenomic” – pieces of messenger RNA that are read by the cell’s ribosomes to produce the viral structural proteins needed to build new viruses.

The virus has evolved a highly efficient process to control the rate of production of these of proteins, coupling them to the supply of viral RNA, so they are made only when they’re needed. This ensures optimum efficiency of the replication process and means that none of the cell’s resources are wasted.

Critically, many of these regulatory processes are unique among RNA viruses and members of the coronavirus family specifically. As such, they represent important targets for the development of antiviral drugs. Examples include the viral proteases involved in cutting up the viral polyprotein, and the replicase transcription complex proteins that coordinate the copying of the viral RNA. 

The final stage is to bring all the components together and assemble the viral particles. This also takes place in the cell cytoplasm and, in a process reminiscent of lowering the engine into a new car, involves uniting the newly-made virus RNA genomes with the viral protein coat molecules. In this way, hundreds of virus particles are produced and released from an infected cell. Some of the released virus will infect neighbouring cells, intensifying the infection, while others are released to the outside world to infect new hosts and spread the disease.

Before the emergence of SARS, MERS and more recently Covid-19,  human coronavirus infections were considered relatively benign respiratory tract infections. Four distinct natural human coronaviruses circulate regularly and are responsible causing self-limiting “common cold” symptoms in a few percent of the population each winter. 

The more severe disease associated with SARS, MERS and the Covid-19 SARS-CoV-2 coronavirus is a consequence of the recent zoonotic spread of these agents from their natural animal hosts - bats (with adaptation in the civet cat in the case of SARS; camels in the case of MERS, and pangolins in the case of SARS-CoV-2) into humans. The high transmissibility of the latter, which is the likely consequence of asymptomatic shedding by infected individuals, has ensured its rapid global spread and designation as a pandemic by the World Health Organisation (WHO).

Although most individuals infected with SARS-CoV-2 exhibit relatively mild disease, between 10-15% develop severe respiratory distress requiring hospitalisation. At present, owing to testing constraints and limited information on the proportion of people infected, it is difficult to determine accurately the mortality rate of the infection. Nevertheless, it is likely that the average mortality rate is <1%, with the greatest mortality observed in the over-70s.

As of 10th April, the WHO have reported 1.5 million Covid-19 cases, with 92,798 deaths globally since the start of the pandemic. Currently, with no vaccine and only limited therapeutic options, most countries have implemented social distancing measures and quarantine procedures to limit spread. Measures including mass testing and contact tracing have also proved to be remarkably successful in both China and South Korea. But these interventions have come at huge economic cost, and in the longer-term strict lockdowns are unsustainable. Instead global efforts are being directed towards the development of effective vaccines and new antiviral medicines, although this will take time and even 1-2 year time scales are likely to be optimistic for full global deployment of an effective vaccine.

A major question that needs to be resolved urgently is what proportion of the general population have already been infected and recovered from SARS-CoV-2. This will rely on the development of accurate tests for the antibodies produced when the body successfully fights off the infection. These tests will need to be rolled out on a mass scale, but the information will be critical to understanding and predicting the likely trajectory of this pandemic and the design of the most appropriate control measures going forward.

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