Battle in blood: Antibody 19/1786 takes on Tick-Borne Virus

Structure and mechanism of Tick-borne encephalitis virus and counteracting antibody 19/1786 are revealed

 One Deadly Bite


Beware!

If you are 1) living in central Eurasia, and 2) a lover of outdoor activities, you might need to be aware of Tick-borne encephalitis virus (TBEV) - a virus, which enters the human body through bites of ticks 2.


Tick (Credit: Image by skeeze from Pixabay) 



Infection with TBEV can be fatal, as it can impair our nervous system by inducing meningitis and encephalitis - over 10,000 cases of infections occur in Europe and Russia annually.


A fatality caused by TBEV infection depends on its subtypes, with the European subtype killing 1 to 2% of patients each year, to up to 20% mortality rate was reported for the Far-East subtype 3.


Dr. Pavel Plevka

 


Yet, for something so fatal, the mechanisms to tackle TBEV-infection remained alarmingly unexplored - that is until the research team of Dr. Pavel Plevka in CEITEC came along.


“We study the structure of the virus, and how it replicates inside a cell,” says Dr. Plevka.


He passionately stresses, “We also describe how a neutralizing antibody (a blood protein that helps with eliminating infectious agents like virus or bacteria) blocks the virus from infecting a cell. 1



Know Your Enemy: Structure and Mechanism of TBEV 


Over the years, in the hope to learn the structure of TBEV, the research team have been using cryo-electron microscopy (used mainly on biomolecules) to image about 4000 virus particles.

This is not as many as it sounds - as TBEV is very small (about 50 nm wide, or 0.00005 mm- while a strand of hair is 1600 times wider at 0.08 mm!) 4.


It is not an easy task to get a clear exposure.

Various electron micrographs from different angles of TBEV

are also needed to put together a 3D model 


Plus, the virus can deviate from its original appearance once it is used for experiments or observation, which makes things more complicated.

Therefore, systematic screening of a large number of virus samples is required for the research.

Dr. Plevka pointed out, “We had difficulty obtaining viruses that are in good condition for imaging, so when we managed to get a high resolution of the virus structure using only 4000 samples, we were all very relieved.”



What did the researchers

see on the final 3D structure of TBEV?



TBEV is spherical in shape, with its surface covered with tiny bridges, named E-proteins, reaching outward. The main purpose of these E-proteins is to bind to a cell, allowing for transferring of genetic information of the virus (called RNA) from within the virus to the newly infected cell.


TBEV turns vicious once it is inside a human cell: after entering, the TBEV is swallowed by a little compartment within the cell (called endosome). The duty of an endosome is to wrap up intruding items, label them to be sorted out and, if necessary, destroy them.


Unfortunately, the acidic pH inside the endosome also unintentionally activates a structural re-arrangement of the E-proteins, exposing tiny loops at their tips that attach the virus to the inside of the endosome membrane.



TBEV virion (Source: Dr. Pavel Plevka)



Once connected, the membrane of the virus fuses with the endosome membrane, merging the virus and the endosomal membranes, and propelling the viral genetic material into the cell’s cytosol. At this stage, the RNA replicates to create more new viruses.

Eventually, the host cell bursts and dies, due to the overwhelming number of new viruses, which far exceeds the cell’s capacity. An army of viruses is now released into the human body, and go on to infect neighbouring cells in the same way, thus infecting the person with TBEV.


Most people infected by TBEV develop minor symptoms, such as fever, headache, fatigue and muscular ache, lasting about 2 to 10 days. During the third and fourth week, about 20 to 30% of patients will suffer from inflammation of the central nervous system. Long-term neuropsychiatric disorders can occur in 10 to 20% of cases 3, 5.



Antibody 19/1786: Possible Lifesaver?


Even though no cure exists, for now, this research might be able to give TBEV-infected patients a beacon of hope- in the form of an antibody named 19/1786.


TBEV virion studded with the 19/1786 antibodies (the golden particles) (Source: Dr. Pavel Plevka)



Employed by our immune system to block bacteria and viruses, each antibody is a Y-shaped lock- with two slots at the top which only specific keys can fit in.


In this case, the slots of antibody 19/1786 fit the surface of TBEV perfectly. By attaching to the virus surface, antibody 19/1786 effectively blocks the virus from clasping onto the inside of the endosome, preventing the viral and endosome membranes from melding together. Trapped inside the endosome with no way to escape, the virus can no longer continue its path of destruction.


Our result regarding both the structure of TBEV and the neutralizing ability of antibody 19/1786 can open doors to design treatments for TBEV-infected patients.” However, Dr. Plevka also reminds us not to be too optimistic, “We are only doing basic research for now and it’s way too early to talk about manufacturing TBEV treatments.”



What Can We Do To Protect Ourselves?  


In the meantime, what can we do to protect ourselves from the infection of TBEV?


Vaccines against TBEV are actually available. But people still get infected, because they are unaware of the vaccines,” Dr. Plevka explains, “some people don’t want to pay, even though they only cost about 30 euro per shot 6,”- which some insurance companies will cover.


Get vaccinated (Credit: Image by Angelo Esslinger from Pixabay) 


Besides price, time is also another issue - it takes three shots to complete the vaccination: the first two shots in a 3-month period, and the third shot in the following year.

Some people just forget or can’t make time for it.

All these reasons contribute to the Czech Republic being one of the most affected countries by TBEV.


In the Czech Republic, only 15 to 20% of people are vaccinated, compared to the hefty 80-90% in Austria” Dr. Plevka adds.


Therefore, to protect the Czech population from TBEV, Dr. Plevka suggests that the government may provide free vaccination to children.

Additionally, the state should put more focus into advertising the vaccines, “The current advertisement by private companies that produce the vaccines is not enough to raise the level of trust and awareness.”


As a word of advice to the public, Dr. Plevka urges: “Get vaccinated!



References

  1. Füzik, T., Formanová, P., Růžek, D., Yoshii, K., Niedrig, M., & Plevka, P. (2018). Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody. Nature Communications, 9(1). doi: 10.1038/s41467-018-02882-0
  2. World Health Organization (2011). Vaccines against tick-borne encephalitis: WHO position paper (pp. 241-256). Genève: World Health Organization. Retrieved from https://www.who.int/wer/2011/wer8624.pdf?ua=1
  3. Signs and Symptoms | Tick-borne Encephalitis (TBE) | CDC. (2014). Retrieved from https://www.cdc.gov/vhf/tbe/symptoms/index.html
  4. Size of the Nanoscale | Nano. Retrieved from https://www.nano.gov/nanotech-101/what/nano-size
  5. Factsheet about tick-borne encephalitis (TBE). Retrieved from https://ecdc.europa.eu/en/tick-borne-encephalitis/facts/factsheet
  6. Prices of vaccines – Travel Medicine Centre. (2018). Retrieved from https://centrumcestovnimediciny.cz/en/prices-of-vaccines/



Written by Sophia Man and Somsuvro Basu


Publication date: 29.03.2019