Investigating tick-borne viruses with mini blood vessels

Raw milk cheeses, global warming and more frequent livestock grazing. What do these things have in common? They all increase the chances of people contracting a virus transmitted by insects or ticks, such as TBE, or 'tick-borne encephalitis'. The disease was first identified in the Netherlands in 2016. After several days of flu-like symptoms, this virus can also cause meningitis in humans, resulting in memory loss and paralysis in the worst cases.

Of every 1,500 ticks in areas such as the Utrecht and Sallandse Heuvelrug, one is infected with TBE virus. The risk of infection is thus much lower than with Lyme disease. The bacteria that causes Lyme is found in 1 in 5 ticks. The big difference: virus transmission often occurs immediately, while it can take hours for bacteria from a tick to transfer to humans. A virus has usually been transmitted long before anyone removes the tick.

Blood vessel-on-a-chip
Since 2025, the Vector-Borne Viruses Expertise Team at Wageningen Bioveterinary Research (WBVR) has been studying that rapid virus transmission in small areas of blood vessels. Virologist Kirsten Bronsvoort shows the culture plate where she grows the mini blood vessels. The plate is barely the size of two smartphones, but contains 96 chips, compartments in which to grow a blood vessel. Each chip has two channels. One channel contains a kind of gel to which cells adhere. In the other channel, Bronsvoort adds endothelial cells that form the blood vessel wall. 

Although Bronsvoort is still setting up the research on tick-borne viruses, the blood vessel model has already been used in research by Melle Holwerda, another virologist and also head of the National Reference Laboratory for vector-borne and zoonotic viral animal diseases. In that second role, he ensures reliable diagnostics for viral diseases in animals and advises the Ministry of Agriculture, Fisheries, Food Security and Nature on suspicions and policy questions. He uses blood vessels to better understand the pathogenic potential of blue tongue virus (BTV). Blue tongue is a viral disease that affects ruminants such as sheep, cattle and goats and is transmitted by midges. The virus is harmless to humans, but animals become seriously ill.

“Several variants of the blue tongue virus have been circulating in recent years. We call these serotypes,” Holwerda explains. “Some of these types are more virulent, i.e. more pathogenic, than other types. This could also be seen in the mini blood vessels.” 24 hours after exposure to the virus, the virus had multiplied and damaged blood vessels. He saw most damage with the most pathogenic virus. 

Holwerda: “This study is the first proof that what you see in the animal can also be mimicked with a small blood vessel in the lab. Such a blood vessel model might be very useful as a first test when a new virus from a tick, mosquito or midge emerges in the Netherlands.” 

The Vector-Borne Viruses Expertise Team closely monitors the presence of viruses transmitted by ticks, mosquitoes and midges. “The TBE virus was first detected in the Netherlands 10 years ago and it is slowly increasing,” says Barry Rockx, senior research associate in Virology and Molecular Biology. “And there are more viruses which are transmitted by ticks and which can be expected in the Netherlands.” 

The Mediterranean tick which transmits Crimean Congo Haemorrhagic Fever (CCHF), for example, now occurs in southern Europe, but is slowly spreading northwards. The tick - still without a virus - occasionally comes to the Netherlands via migratory birds. And mosquitoes also pose a risk, according to Rockx. "The West Nile virus, which is transmitted by mosquitoes, was detected in the Netherlands for the first time in 2020. The mosquitoes that transmit Rift Valley fever are present in the Netherlands, but the virus itself is not yet."

Rockx and Bronsvoort show ticks collected in the field at a WBVR laboratory in Lelystad. They are under the microscope and secured with double-sided tape. The ticks, some nearly a centimetre long and bulging with blood, have been found on cattle, in pastures and in surrounding forest areas. “We still don’t know much about ticks feeding on farm animals. There has been much more research on wildlife in recent years, but farm animals are becoming an increasingly important host. Livestock are also grazing outside more often these days, sometimes in systems where agriculture and nature merge. And it is not yet clear how ticks transmit viruses at different life stages. That is why we examine both juvenile and adult ticks,” says Rockx. They get blood meals from a jar with a membrane they can actually bite into. 

Captured ticks could therefore be infected. “We use a PCR test to check whether there is genetic material from a tick virus in a tick,” says Rockx. (PCR is a method to find specific fragments of DNA and became known to the general public during the Covid pandemic, but has been widely used for genetic research for some time, ed.) Precautionary measures also apply to ticks that have been deliberately infected with a virus by the researchers. This takes place in the High Containment Unit, where protocols apply with airlocks, showers, see-through tents and protective suits.

These infected ticks are needed for animal studies, for example. The researchers put the ticks on mice to study virus transmission. Because all aspects of that interaction are involved, from the tick's saliva to the host's blood, it is necessary to work with real animals. But ideally, researchers minimise animal testing. “A mouse is not a sheep or a human, so not everything will work the same, and from an ethical point of view it is good to replace and reduce animal testing where possible,” says Rockx.

Rockx, Holwerda and Bronsvoort expect mini blood vessels to speed up research. They also hope to find biomarkers in the blood, substances that ‘indicate' the characteristics of a virus. Holwerda: “You then know earlier in an outbreak what type of virus you are dealing with, including how pathogenic it is.” “And it helps,” adds Rockx, “us better understand the mechanism of virus transmission. Say you have 10 options for vaccines or drugs that act on that mechanism, then you can make an initial selection for further research more quickly.”