How to track down a new virus – and link it to disease

By Anthony King

Finding new viruses is easy – the hard part is understanding which ones cause disease, says Dr Lia van der Hoek, a virologist from the Amsterdam UMC, the Netherlands, who discovered a human coronavirus called NL63, in 2003.

She suspects that not all viruses may be harmful and that having a diverse collection of viruses in the human body may even be beneficial, but this is an open question, she says.

You hunt viruses in both humans and animals. What makes viruses so intriguing for you?

I want to find the cause of a disease for which people do not know the cause yet. Knowing the cause provides options for treatment. If a disease is caused by a virus, I want to find it.

Can you give us an example of a virus you’ve found?

I found a new human coronavirus, NL63, in 2003. We now know that this is a typical winter virus that infects children around January and February. Often children will have antibodies to this NL63 coronavirus before age two. Adults also get infected throughout life. This NL63 coronavirus usually causes typical common cold symptoms, such as a runny nose, sneezing, a sore throat.

How did you go about finding the NL63 virus?

My identification of a new coronavirus started with a child seen in a hospital in the Netherlands who was sick with bronchitis and conjunctivitis. The child was not severely ill and was sent home and monitored. But (the hospital) collected a sample (from the child’s nose).

There was a suspicion that it was an infection with RSV (respiratory syncytial virus), yet when the lab tried to detect RSV this turned out negative. Then all the other respiratory virus tests were done and these were also negative. The laboratory from the Municipal Health Service of Amsterdam asked me to see which virus was infecting the cells. I found a coronavirus and named it NL63 in April 2003.

How do you go about identifying a virus?

Back then there was no next generation sequencing like today. I had to develop my own techniques to find new viruses, when I started hunting for them in 2001. At the time, we had no clue about the proteins or genetic code of unknown viruses.

First, we know viruses are small, so you select out things that are 100 or 200 nanometres. Then I multiplied DNA or RNA present in a sample. After that, I used restriction enzymes from bacteria that chop up specific small genetic sequences. Comparing the code of these small fragments with the viruses we already know then shows whether the virus may be a new one.

How did you work out it was a coronavirus?

Once I (did the sequencing), I discovered that the code resembled other coronaviruses, but was different enough to be new.

In that same year, there was an outbreak in China, Hong Kong, with an overflow to Canada. It took two to three months to find the virus that caused that epidemic, which was SARS. When I first got the sequence of NL63, I saw that it was similar to the (SARS) virus and I knew immediately that this was important.

There were only three known human coronaviruses before NL63, the other common cold viruses OC43 and 229E, and SARS coronavirus.

How does your approach differ from that of other virus hunters?

Today, virus hunters can easily sequence hundreds of unknown viruses by taking samples from the oceans or soils or animals. Most virus discoverers usually publish on a new virus, and how it looks, and then continue on to the next virus. Searching for unknown viruses is not difficult, but finding new relevant viruses is. That is why I only search for new viruses when I am in contact with medical doctors that see a disease in patients and that disease seems to be infectious.

Because of that, I was interested in how NL63 works, and so I ended up publishing around 30 studies on NL63 and other (human) coronaviruses. I enjoy determining what disease a new virus causes and how often it occurs.

What other viruses have you discovered?

We discovered a lot more viruses since NL63. Another I found was in sea bass and turned out to cause scale-drop disease. It was an iridovirus and caused a devastating disease in Asian fish farms. We grew up the virus (in the lab) and I worked with a company that managed to make a vaccine that could prevent the disease in fish.

Which viruses are more likely to spill over to people and cause disease?

Another coronavirus or an avian influenza virus. They are the most dangerous. Birds can shed avian flu viruses. They can latch onto receptors in our lower respiratory tract, so spillover is easy for them, but they don’t easily transmit from human to human. In bats, there are so many coronaviruses, and they can shed them.

Where did NL63 come from?

Most likely bats, because NL63-like sequences are in a bat. Though I did not sample or screen bats. We know NL63 attaches to the ACE2 receptor (like SARS-CoV-2). The bat ACE2 receptor looks a lot like human ACE2, so it is not strange that bats were also the source of NL63 coming to humans.

Are viruses always bad?

I have the hypothesis that some viruses may be beneficial. I have no proof. It is only a hypothesis, simply because some viruses fail to be associated with disease, so these viruses may be beneficial, but this has not been investigated yet. Work on this topic is ongoing in my group.

So some viruses that live within us do not cause disease?

There are lots of viruses in our gut and lots of novel viruses in our stool. Whether they interact with the bacterial community in the gut is unknown (some viruses specifically target bacteria and kill them, and in this way could influence the makeup of our gut microbiome). It is nice to speculate that these viruses are there to help us, that they are part of us and we cannot live without them, but that is unknown. There is also a virome in our blood, so inside our bodies. These are called orphan viruses, because they are not linked to a disease. I would love to find out if we are healthier when we have a diverse virome.