How the COVID-19 virus infects you (and others)

The way in which the virus that causes COVID-19, called SARS-COV-2 causes disease and has higher infectivity is now starting to get better understood.

The body would appear to have two distinct processes that are both equally important in allowing the virus to find and then gain access into specific types of cells. The two processes are:

1. Showing the virus the way to the target cell, and

2. Allowing cell attachment and viral entry

Understanding these processes and fully characterising the mechanisms are fundamental to indicating appropriate therapeutic approaches, finding methods to block viral uptake and suggesting target molecules for protective antibodies (vaccines).

A nose for detection

As is often the way with good science, many breakthroughs start by making important observations. The history of medicine is full of such stories. For example, when John Snow observed that the majority of cases of cholera in London were associated with people travelling to the same water pump in Soho, or when Alexander Fleming noticed the death of bacteria around rogue fungal growths on his petri dish in his lab on Praed Street, Paddington.

Is viral infectivity related to the upper or lower respiratory tract?

The observations that have underpinned the latest work recently published in the journal Science may well turn out to be as significant.

The observation is this; loss of smell is among the COVID-19 symptoms

There then follows some scientific and biological logic:

1. Upper respiratory tract infections and rapid viral shedding

The degree to which a virus spreads depends on its infectivity. While the coronavirus SARS-COV-2 has led to a pandemic, a related virus, SARS-COV, led to a much smaller outbreak in 2003, possibly because the infection was limited to the lower respiratory system. SARS-COV-2 in contrast, infects the upper portions of the respiratory tract, including the nasal mucous membrane and, in consequence, spreads rapidly through active viral shedding.

High levels of virus have been found in the mouths and noses of patients with active SARS-COV-2 infection, to the extent that some research has pointed to the role of mouthwash.

2. Differences in the viral spikes

There are viral access points on the surfaces of our cells with regions known as 'receptors', which if the viral spike is the key - then the receptor is the lock. These locks are necessary to provide the entry of a specific virus type into the cell. Both SARS-COV and SARS-COV-2 have a type of lock (or receptor) known as 'ACE2'. However, despite both using the same lock, infection results in a different type of illness. In order to understand why the two related viruses infect different types of cells, the researchers took a look at the viral “spike proteins” that are essential for virus entry.

The structural spikes that are seen surrounding the viruses act as a type of key that will only open one type of lock, and so entry to the cell depends on whether the cell has the right lock on it's surface i.e. ACE2. Interestingly, the researchers found a difference in the structure of the viral spikes meaning that SARS-COV-2 and it's older relative SARS-COV have different keys and enter different cell types.

3. The different viral spike interacts with a protein that likes the brain and is found in the nasal cavity.

To determine where a virus might get cell access there is also a protein called neuropilin-1. This protein enables SARS COV-2 cell entry by showing the virus the way to the target cell. This protein is present in the mucous membranes of the nose (olfactory) and upper respiratory tract. Neuropilin-1 may also be involved in transporting virus to nerve cells - and also to the brain.

Nose, neuropilin-1 to brain

So, since loss of smell is among the COVID-19 symptoms and neuropilin-1 is found in the cell layer of the nasal cavity, the scientists wanted to find out, "whether cells equipped with neuropilin-1 are really infected by SARS-COV-2", and they have indeed found this to be the case.

There is still a lot of research to be done, but the findings do suggest that the protein neuropilin-1 could be the correct passkey to open the door and then onto the cell's interior. These observations would seem to make neurophilin-1 a good target for additional research.

Lead researcher, Prof Mikael Simons, from the Technical University of Munich (TUM) says,"The SARS-COV-2 spike protein differs from its older relative by the insertion of a furin cleavage site". When proteins are cleaved by furin, a specific amino acid sequence is exposed on the cleaved end. These furin-cleaved substrates exhibit a characteristic pattern, which is known to bind to neuropilins at the cell surface.

Infection suppressed by blocking neuropilin-1 with antibodies

Experiments using cells cultured in the laboratory, in conjunction with artificial viruses that mimic SARS-COV-2 as well as naturally occurring virus, indicate that neuropilin-1 is able to promote infection in the presence of ACE2. By specifically blocking neuropilin-1 with antibodies, infection was suppressed.

Prof Simons says, "If you think of ACE2 as a door to enter the cell, then neuropilin-1 could be a factor that directs the virus to the door. ACE2 is expressed at very low levels in most cells. Thus, it is not easy for the virus to find doors to enter. Other factors such as neuropilin-1 might be necessary to help the virus," 

Possible path into the nerve tract and brain:

Additional experiments showed that neuropilin-1 enables transport of tiny, virus-sized particles from the nasal mucosa to the central nervous system. "We could determine that neuropilin-1, at least under the conditions of our experiments, promotes transport into the brain, but we cannot make any conclusion on whether this is also true for SARS-COV-2. It is very likely that this pathway is suppressed by the immune system in most patients," 

Is there a new approach for treating COVID-19?

"SARS CoV-2 requires the ACE2 receptor in order to penetrate cells, but other factors such as neuropilin-1 are possibly needed in order to support its function," says Prof Simons. "Currently, we can only speculate about the molecular processes involved. Presumably, neuropilin-1 catches the virus and directs it to ACE2. Further investigations are needed to clarify this issue. It is currently too early to speculate whether blocking neuropilin could be a viable therapeutic approach. This will have to be addressed in future studies."

An abbreviation for angiotensin-converting enzyme Full medical glossary
An organic compound that is the basic building block of all proteins. Full medical glossary
Special proteins in the blood that are produced in response to a specific antigen and play a key role in immunity and allergy. Full medical glossary
A group of organisms too small to be seen with the naked eye, which are usually made up of just a single cell. Full medical glossary
The basic unit of all living organisms. Full medical glossary
The growth within a laboratory of microbes, organisms too small to be seen with the naked eye. Full medical glossary
The organs specialised to fight infection. Full medical glossary
Invasion by organisms that may be harmful, for example bacteria or parasites. Full medical glossary
Membranes that line many body structures such as the respiratory tract and the gastrointestinal tract and produce mucus. Full medical glossary
Relating to the nose Full medical glossary
Bundle of fibres that carries information in the form of electrical impulses. Full medical glossary
The system that gathers and stores information and is in overall control of the body. The brain and spinal cord form the central nervous system. Full medical glossary
An outbreak of infection that affects numerous people in different countries. Full medical glossary
Compounds that form the structure of muscles and other tissues in the body, as well as comprising enzymes and hormones. Full medical glossary
The parts of the body that are involved in respiration. The respiratory tract includes the nasal passages, throat (pharynx), windpipe (trachea), bronchi and lungs. Full medical glossary
septic arthritis Full medical glossary
Capable of survival. Full medical glossary
A microbe that is only able to multiply within living cells. Full medical glossary
Microbes that are only able to multiply within living cells. Full medical glossary