Coronavirus pandemic progress report

Within eight months, the novel coronavirus SARS-CoV-2 and the disease it causes, COVID-19, dominated the work of thousands of researchers in an unprecedented global effort.

In a series of editorials, we look back on key scientific findings that have revealed important features of the virus and COVID-19, including new approaches to treatment and prevention. We start this week with how the virus was identified; molecular details of its mechanism of infection; how it is transmitted between people; and the many ways it affects the human body.

Crack the virus code

When an outbreak of a disease similar to Severe Acute Respiratory Syndrome (SARS) emerged in Wuhan, China in late 2019, researchers suspected that a new coronavirus had spread to humans. Many of the first cases identified were linked to a single live animal market in the city.

Chinese researchers immediately began work to isolate and sequence the virus. When the original SARS virus, now known as SARS-CoV-1, appeared in humans in 2002, it took months to get a complete sequence of the virus’s genome. This time around, advances in sequencing technologies have allowed scientists to crack the RNA code of the virus within weeks of the appearance of the first cases.

On January 11, Yong-Zhen Zhang of Shanghai Fudan University and his colleagues deposited the genomic sequence of a virus isolated from a 41-year-old man who had worked at the animal market into a public database. In doing so, they alerted the world to the existence of a novel coronavirus linked to SARS-CoV-1. Their findings were then published in Nature¹.

Although Zhang’s team only sequenced the virus in one patient, concurrent work from other groups identified the same virus in other people with pneumonia. Together, these researchers have firmly implicated this novel coronavirus as the cause of the disease. One of the teams, led by Shi Zhengli at the Wuhan Institute of Virology, also determined that the new virus’s known closest relative was a bat coronavirus.².

Some six months later, the coronavirus ravaged the world. Scientists have now generated more than 80,000 viral sequences. This wealth of genetic information has made it possible to trace the chains of transmission – revealing, for example, cryptic community transmission in the United States – as well as showing that a variant that appears to be particularly infectious to cultured cells has now become dominant. in the world.^3,4. What this altered infectivity means for transmission and disease is not yet clear.

Not just a respiratory virus

The first reports of the disease, named COVID-19 on February 11, described severe respiratory illness similar to that caused by SARS-CoV-1. Chest scans have shown patchy shadows – called “ frosted glass opacities ” – in the lungs of many patients, according to initial studies from Wuhan hospitals⁵. Additionally, older people, men, and people with other illnesses were more likely to be admitted to intensive care, while children appeared to have milder illness.⁶.

But it quickly became clear that SARS-CoV-2 is not just a respiratory virus. It also affects the blood vessels, causing thrombosis⁷ and blows⁸. In rare cases, children can develop what is called multisystem inflammatory syndrome, reminiscent of Kawasaki disease.⁹.

Autopsies found the virus in organs other than the lungs, including the kidneys, liver, heart and brain, as well as in the blood^ten. We now know that symptoms of COVID-19 can include gastrointestinal, neurological, kidney, cardiovascular and other complications.¹¹.

Symptoms experienced by different people may be dictated by a combination of infected cells and tissues; the direct damage that the virus causes to these cells; interference with the normal function of ACE2 receptors in host cells to which the virus binds; and individual variations in the immune response to the virus. For example, critically ill patients show an overactivation of their immune response, which damages the lungs.

We hope that revealing these contributions will lead to effective treatments. The steroid drug dexamethasone, which calms the overactive immune response, has previously been shown to reduce mortality from severe COVID-19¹². Progress has also been made in the management of serious illnesses. However, the causes of the sudden onset of acute respiratory distress in some people are still unknown.

Modes of infection

A burning question at the start was how the new virus infects human cells – the answer would help explain the pathology of the disease, while also offering clues on how to block the infection.

Coronaviruses are decorated with “spike” proteins. These interact with specific proteins on the surface of the cells they infect. After binding to the cell receptor, the peak must be cleaved by an enzyme called a protease in the host cell. This activates the peak, which fuses the virus and cell membranes.

Scientists quickly showed that SARS-CoV-1 and the novel coronavirus use the same cellular receptor, ACE2², and the same protease, TMPRSS2¹³, to enter cells. But SARS-CoV-2 can also infect cell lines that do not express TMPRSS2, which could hold back drug development.

Researchers used Vero cells – which do not express TMPRSS2 – in an initial study suggesting the drug chloroquine may work as a treatment for COVID-19¹⁴. But chloroquine has not been shown to be effective in clinical trials, and scientists have found that it does not inhibit the virus in lung cells that express TMPRSS2.¹⁵.

Despite the overall structural similarity between the peak proteins of the two SARS coronaviruses, the scientists found that the SARS-CoV-2 peak binds to the ACE2 receptor at least ten times more tightly than SARS-CoV-1.¹⁶. This could explain some of the differences between the way the two viruses infect people and cause disease.

The SARS-CoV-2 spike also has a feature that SARS-CoV-1 lacks: an amino acid sequence that allows it to be recognized and cleaved by an enzyme called furin.¹⁷. It is not yet known how this sequence contributes to the virulence of SARS-CoV-2. But similar sequences are also found in the receptor binding protein of some influenza viruses and contribute to their virulence.

Something in the air

It soon became clear that SARS-CoV-2 could pass from person to person. This can occur by direct contact or by indirect transmission, such as droplets expelled during a cough, or even by a simple exhalation. What was not clear – and is still the subject of debate – is the size of these droplets and the distance they can travel.

This is an important question. Larger droplets will quickly fall to the ground, but smaller, lighter ones – called aerosols – can stay suspended in the air. A virus that can hitchhike with such tiny droplets can travel further and increase the risk of infection in poorly ventilated indoor spaces.

The potential of the novel coronavirus to travel this way was the subject of a study, published in April, on the aerodynamics of SARS-CoV-2 at two hospitals in Wuhan¹⁸. Researchers found that some areas of hospitals, especially some areas of staff, had relatively high concentrations of viral RNA in aerosol-sized droplets.

The team did not determine if these droplets were infectious, but a US-based team reported in April that SARS-CoV-2 and SARS-CoV-1 were stable and infectious in artificially generated aerosols during three hours.¹⁹.

It has not yet been definitively shown that SARS-CoV-2 spreads in this way, in part because it is difficult to measure the different routes of transmission of the virus separately.

Invisible disease

As the virus began to spread around the world, it was suggested that people without symptoms might be able to pass it on.

In March, data from the Diamond Princess cruise ship revealed that 17.9% of people who tested positive for COVID-19 on the ship had no symptoms²⁰. More than 3,700 people were quarantined aboard the ship in February after the discovery of a former passenger carrying COVID-19. In April, a study of 94 people showed that “ viral shedding ” – the release of a virus into the environment – seemed to peak before or at the same time as symptoms appeared.²¹. The researchers also evaluated 77 pairs of people, one of whom had likely been infected by the other, and found that 44% of infections were transmitted before participants developed symptoms.

The proportion of virus carriers who never show symptoms is still a matter of debate, but it is clear that people can transmit the virus even if they are not sick, which is likely contributing to its spread.

We’ve come a long way to understand how the pandemic came about and how it spread around the world – by studying the characteristics and transmission of the virus, and how it causes disease. In future issues of this editorial series, we’ll look at the research on how to control it, as well as advances in treatments and vaccines.