From the common cold to the deadly pneumonia, what determines the intensity of the coronavirus?

Since the first detection of the human-infected coronavirus in the 1960s, we have identified seven infectious coronaviruses – four milder, while three of the two (SARS, MERS and new coronaviruses) that have emerged this century have led to deadly outbreaks. How do some coronaviruses evolve to be deadly? Why do different types of coronaviruses cause very different symptoms and severity when they infect a human body? What are the characteristics of the new coronavirus compared to the previous coronavirus? This article will analyze these coronaviruses from a molecular biology perspective.

From the common cold to the deadly pneumonia, what determines the intensity of the coronavirus?

Coronary virus schematic (Photo: 2020 Maurizio De Angelis)

Many people may not be familiar with the concept of “coronavirus”, but in fact, most people have been infected with coronavirus. About one in five common colds are caused by four milder coronaviruses. There are also coronaviruses that are transmitted in specific animals. But at least 20 years ago, all coronaviruses that could infect humans were mild, so scientific research on them was stagnant.

It wasn’t until 2003, when researchers detected that the virus that caused Severe Acute Respiratory Syndrome (SARS) in China was a brand new coronavirus, the previous calm was completely broken. Susan Weiss, a microbiologist at the University of Pennsylvania, said: “At the time, all the researchers in this field were shocked and they started to really pay attention to these viruses. “It is believed that the outbreak of SARS was caused by a coronavirus that was originally transmitted from animal to animal, transmitted to humans through beavers. And in 2012, another new coronavirus was transferred from camels to humans, leading to a Middle East Respiratory Syndrome (MERS) outbreak that once again confirmed that the deadly coronavirus can be transmitted from animals to humans. The original MERS outbreak in Saudi Arabia resulted in 858 deaths, with a fatality rate of 34 per cent.

Currently, researchers can almost confirm that the SARS virus, MERS virus and this new coronavirus (2019-nCoV) all originated from bats. Analysis of the 2019-nCoV genome showed that viral RNA sequences were 96% similar to a coronavirus present in bats. Stanley Perlman, a microbiologist at the University of Iowa, says these coronaviruses have been around for a long time in bats but do not cause disease in bats. Current researchers believe that the new coronavirus is more likely to be transmitted to humans through some intermediate host. The previously infected coronavirus also seems to have gone through the process. In these intermediate hosts, coronaviruses undergo multiple genetic variants and have higher genetic diversity.

What exactly determines when and how the coronavirus is transmitted to humans, and how contagious is? How do coronaviruses cause these infections? Why do some coronaviruses only cause cough symptoms in infected people, while others are so deadly? Scientists have been trying to answer these questions since the coronavirus first posed a serious global health threat 17 years ago.

The structure of coronaviruses

Coronary viruses are a class of single-stranded RNA viruses with encapsulation, which means that their genomes consist of a single strand of RNA (not DNA), and each virus particle is encased in a protein “encapsulation”. All viruses are basically doing the same thing – invading cells, controlling some of the components of the cells for their own replication, and then new viruses escape from the cells and infect other cells.

However, the mechanism by which DNA replication errors are repaired in cells does not repair viral RNA, so the replication process of RNA virus genes often goes wrong. Of all RNA viruses, the genome of the coronavirus is the longest – it consists of 30,000 bases, and the more bases the virus needs to replicate, the more likely it is to make a mistake. As a result, these coronaviruses are highly variable. Because of the frequent variation of the genome, coronaviruses may acquire new characteristics, such as the ability to infect the host with new cell types, or even the ability to infect new species.

Coronary virus particles contain four structural proteins, namely, nucleoid protein, encapsulation protein, membrane protein and protrusion protein. The nuclear crust is the core structure of the genetic material that wraps the virus, which is encased in a sphere of enveloping proteins and membrane proteins. The protrusion protein forms a stick-like protrusion structure on the surface of the virus. Coronary viruses are named precisely because of these forms similar to the protrusions of the crown or corona. These protrusions bind to receptors on the host cell, determining the type of cell that a virus can infect and the range of species that can be invaded.

Coronary viruses that cause colds mainly infect the upper respiratory tract of humans, such as the nose and throat. The potentially deadly coronavirus can infect the lower respiratory tract, such as lung cells, and cause infections that can cause pneumonia. The researchers found that the SARS virus binds to one ACE2 receptor, while the MERS virus binds to another DPP4 receptor, both found in places such as the surface of lung cells. The difference in the distribution of these two receptors in tissues and organs may explain the difference between the two diseases. For example, MERS has a higher fatality rate than SARS and can lead to more obvious gastrointestinal syndrome, but the MERS virus is not highly contagious and may also be related to the receptor characteristics of its infection.

Christine Tait-Burkard, a virologist at the University of Edinburgh, said: “DPP4 receptors are abundantly present in cells in the lower branch of the bronchial tube, and human airways are very good at filtering out pathogens. Therefore, only a large number of MERS virus into the human body, it is possible to make the virus reach the lungs, infecting humans. This also means that the body needs to be exposed to high concentrations of the virus for a long time (the virus can reach the lungs), which is why people who come into close contact with camels are infected with merS. “

Conversely, viruses replicated in the upper respiratory tract are more infectious because pathogens can enter and leave the body more easily in the upper respiratory tract. “The ability of viruses to replicate at different temperatures is also an important factor,” Tait-Burkard added. “The lower respiratory tract is a more hostile environment for these viruses, both from a biochemical and immunological perspective.

Analysis of 2019-nCoV showed that the new coronavirus, like SARS, enters the cells through ACE2 receptors. This observation is also consistent with the fact that, so far, the new coronavirus is less lethal than MERS. (Currently, the new coronavirus mortality rate is about 2%, but this number may change as the outbreak develops and more cases are detected.) )

Although different coronaviruses can infect cells with the same receptors, the diseases that can cause are quite different. NL63 is a coronavirus that can infect humans, and it binds to the same receptor as the SARS virus, but only causes upper respiratory tract infections. The SARS virus mainly infects the lower respiratory tract of the human body. “We don’t know why this is happening,” Perlman said. “

Another strange phenomenon is that heart cells also have a large number of ACE2 receptors on the surface, but the SARS virus does not infect heart cells. “These studies clearly show that other receptors or auxiliary receptors are involved in the infection process of the virus,” said Burtram Fielding, a molecular biologist at the University of the Western Cape in South Africa. “Binding to a receptor is only the first step for a virus to enter a cell. When a virus binds to the host cell, they form together, and the rest of the viral proteins may bind to other receptors in the cell. “To improve the efficiency of entering cells, viruses may bind to other receptors in addition to the primary receptors,” Fielding said. “

Escape from the immune system

Another important feature of coronaviruses is that their “auxiliary” proteins help the virus evade the host’s innate immune response, the body’s first immune line. When a cell detects a virus invasion, it releases interferon to initiate an immune response. These interferons interfere with the replication of pathogens in host cells and trigger antiviral cascading immune responses, including terminating protein synthesis in host cells and inducing apoptosis. However, most of these immune responses also adversely affect the host. “Many diseases occur because of the immune inflammatory response and the destructive substances that the virus causes,” Weiss said. “

To date, most patients who die from new coronaviruses “have complications, such as autoimmune diseases or secondary infections.” Once the body’s innate immune system is busy fighting the virus, the symptoms of other diseases may be more severe,” Tait-Burkard said. “

Some viruses have also evolved characteristics for the body’s immune response to remove the virus. These characteristics may be the biggest difference between different coronaviruses. “Although these viruses are closely related, they have different auxiliary proteins,” Weiss said, adding that these coronaviruses “have evolved the ability to shut down multiple innate immune responses in humans.” “

Some researchers believe that bats can coexist with coronaviruses because they do not react strongly to coronaviruses like humans do. “Bats suppress a variety of signaling molecules in the body that trigger an immune response, so they don’t get sick,” Tait-Burkard said, noting that bats maintain a constant low-level immune response compared to a strong immune response, which may promote the evolution of the virus.” So the viruses that can escape this immune response were screened. Bats are a very good screening host, and it’s all those viruses that survive in their bodies that are good at hiding. “

However, the researchers do not know enough about coronavirus-assisted proteins. “These auxiliary proteins are taken out of some viruses, and the growth of the virus will not be affected,” Perlman said. But that is not the case. Some researchers believe that these complementary proteins affect the lethality of coronaviruses. Their research on sars viruses showed that removing auxiliary proteins does not change the efficiency of virus replication, but reduces pathogenicity. “While viruses still replicate in large numbers within the host, the damage is less,” Fielding said. “

Coronary viruses have the ability to correct genetic errors, but they ignore certain areas of the genome, Tait-Burkard said. As a result, there are two areas of the coronavirus genome that are prone to mutation, namely, the gene region that encodes protrusion proteins and auxiliary proteins. “Because coronaviruses try to bind to new receptors to evade the immune response, many replication errors that coronaviruses produce in both gene regions can contribute to virus evolution,” Tait-Burkard said. This is why coronaviruses are highly capable of transmitting from one species to another. “