Even the common cold causes hefty economic losses, says virologist Pavel Plevka

Virology has a long tradition in Czech academia and Pavel Plevka is currently one of its most distinguished representatives. After many years spent abroad, he put down roots in CEITEC, a research institute in Brno that is part of Masaryk University. He studies tiny RNA viruses called picornaviruses that cause a range of conditions from encephalitis to the common cold – which, as it turns out, is not all that common: its economic impact is huge.

Read the story in Czech translation here.

Pavel Plevka became one of the most frequently cited Czech virologists during the pandemic – albeit in the mainstream Czech media. 

Although these citations do not count towards his citation index, he doesn’t need to lose any sleep over it. His publications in high-impact journals such as Science, PNAS, Science Advances and Nature Communications brought him global renown a long time ago.

Despite his success, he still finds giving interviews stressful. “I’m worried whether what I say makes sense and that it’s comprehensible. Unfortunately, the experts’ responses to the Covid-19 pandemic were not coordinated and often contradicted each other, which only added to the high level of noise in the media messages. I tried to avoid contributing to that,” he says, looking back at his recent media exposure. 

And I dare say his effort was successful. I can still remember how I felt when reading the interview he gave to my colleague Adéla Skoupá, which was published in Deník N last March, at the onset of the pandemic in Czechia. He said that we were in for at least eighteen months of tightening and loosening of restrictions and I hoped he was wrong.

He could not have been more right.

As he admits, the boldness of his statement made him pause for a while. “Then I thought it over once again and stood behind what I said: it could not have been any other way. This is not about the virus, it’s about people. I gained some insight into how decisions are made in the Czech Republic, and it wasn’t a pleasant sight. The political decisions came late and were made by the prime minister’s PR team,” he recounts.

Today, he is much more relaxed and jovial at our interview than I remember him from our meeting four years ago, and he also seems to speak more freely. He has obviously become much more used to talking to the media.

How about deploying viruses to fight against cancer?

Pavel Plevka was born and raised in Prague. He was interested in nature from a young age and once he finished grammar school, his future was inevitably bound to the study of life sciences. “I had this great idea that viruses could be used to treat cancer! And then I enrolled at university and discovered that someone else came up with this idea a while ago,” he says with a smile.

Although his idea fell flat, he was still drawn to viruses. At one point, he toyed with neurology, but once he became part of the virology group led by Associate Professor Jitka Forstrová at the Prague Faculty of Science, it was a done deal.

The world of viruses drew him in and never let him go. “Professor Forstrová had a huge impact on my career. She is genuinely enthusiastic about virology and a great lecturer, particularly on the molecular biology of viruses, and she leads one of the best research groups at the Faculty of Science.”

It is perhaps not surprising that Professor Forstrová’s inspiring personality also had a strong impact on others. Zuzana Kečkéšová, who received an exceedingly generous private grant to study cancer several years ago, and Evžen Bouřa, whose research includes SARS-CoV-2, were also among her students. Both work at the Institute of Organic Chemistry and Biochemistry.

After completing his master’s degree in Prague, Pavel Plevka left for Sweden to earn his PhD. “There is a well-respected centre of protein crystallography at the University of Upsalla where they developed programmes for processing crystallographic data. My PhD supervisors, Lars Liljas and Kaspars Tars, taught me how to use crystallography to determine the structure of icosahedral viruses and prompted my research focus on the structural biology of viruses.”

He laughs as he recalls the conversations with his parents: “Before I left for Sweden, I was keen to explain to my parents the gist of my PhD studies. As I was getting more and more desperate, my explanations were becoming increasingly simplified, until one day I overheard my mum saying to her friend over the phone that I was going to Sweden to crystallise meat! On the other hand, my pandemic stints in the mainstream media were, obviously, indefinitely more interesting to my parents than my research publications.”

In 2009, Pavel Plevka headed to the USA, where he obtained a postdoc position at Purdue University in Indiana. His future wife, Zuzana Ringlerová, was then a political science student at the same university.

“At Purdue, I worked in Michael Rossmann’s research group. He showed me what passion for science really looks like and how determined you can be to obtain interpretable experiment results. I liked the way he led his research group and I’m trying to emulate his example in my own team at CEITEC.” He returned to the Czech Republic in 2013.

The Holy Trinity 

As I mentioned, I first interviewed Pavel Plevka four years ago. Back then, he mentioned the Holy Trinity of factors that stopped the mass deaths from diseases prevalent in the past: hygiene, antibiotics and vaccines.

This prompted me to ask whether he was frustrated by the current lack of interest in vaccines and the highly infectious nature of myths and false information? “For many people, rational arguments are simply not enough to quell their fear of the vaccine. My colleague, Jiří Nantl, made an interesting observation: people are willing to accept months of lockdown, closed restaurants and travel bans, but they are not willing to get vaccinated. The Sars-Cov-2 vaccines are first-class with high levels of protection and any more serious adverse effects are very rare. From now on, natural scientists can only play a marginal role; we need social scientists, who study people and societies, to find a way to overcome those fears,” says Pavel Plevka. “We need a good marketing campaign that will take people’s emotions into account – even the irrational ones.”

As a structural virologist, Pavel Plevka considered whether to join the research into the novel coronavirus with his CEITEC lab. This was back in January 2020, in the early days of the pandemic.

“I felt that it was going to be a race. There was potential for great results, but I wasn’t sure whether we could arrive at them faster than the US and Chinese researchers. We would have had to abandon everything that we were working on and focus solely on the coronavirus,” he explains.

He decided to keep working on the projects that were already under way and that formed the basis of his students’ and postocs’ theses and to follow the coronavirus developments only as an avid viewer.

From the common cold to the fizzy bomb 

Pavel Plevka is an expert in a different type of viruses: the picornaviruses, or miniature RNA viruses. Some of them cause the life-threatening encephalitis while others are “only” responsible for the common cold.

Although the common cold appears to be a pretty banal condition, at least for someone with a good immune system, it is not actually that benign. “If you catch it four times a year and each time it limits what you can do or even puts you in bed for a few days, the global economic loss is overwhelming – both for the regular female cold and for the man flu, although otherwise, they are obviously two very different categories,” he adds, expertly. 

He notes that since there are no antivirals for the common old, we can only alleviate the symptoms, so research into these viruses could help develop actual treatment.

Between 2014 and 2019, his picornavirus research was supported by an ERC grant; now he is continuing with an EXPRO grant from the Czech Science Foundation. 

His team initially focused on human picornaviruses but have since shifted focus onto the viruses that decimate bee populations. They have already described their structure and the mechanism that allows them to attack cells and spread their genetic information.

Obviously, the ultimate goal of this research is an effective treatment for bee colonies. “So far, we are striking out. Together with Associate Professor Antonín Přidal from Mendel University, we have been testing substances that work against human picornaviruses but these have always turned out to be ineffective or even poisonous to bees.” 

One dead end after another.

However, describing the no-gos is one of the principles of science and learning. While only a few researchers are lucky enough make a breakthrough discovery, someone has to find all the dead ends or else we would wander around in circles and science could not move forward. Besides, Pavel Plevka has a lot more home runs than strikeouts.

One example: when studying picornaviruses with a cryo-electron microscope (a device Pavel Plevka is proud of and also fond of describing its advantages), he and his team found that the picornavirus particle, a tiny virus ball, binds to the cell surface and is eventually absorbed into the cell...

...which is something that was described before... 

...but at one point, the picornavirus then suddenly lifts out a piece of its protein shell and its genetic information jumps out into the cell. 

In his description of the virus, Pavel Plevka compares it to the Pac-Man video game from the early 1990s. Pac-Man was a ball-shaped character with a wide-open slit-like mouth.

Another good comparison that Pavel Plevka used in the past is a fizzy bomb that you can make with the yellow plastic capsule contained in a chocolate egg. “When you fill it with water, add some baking powder and quickly close it and throw it away, the capsule cannot withstand the pressure of the chemical reaction and explodes – the two halves separate and the content bursts out. The picornavirus uses a similar mechanism to get its genetic information out into the cell.”

As the father of two boys, he has since discovered that while the current version of chocolate eggs still contain toys in a yellow plastic capsule, there is now a hinge that holds both parts of the capsule together when opened. 

While this makes the fizzy bomb slightly less impressive, it is still a good description of how the picornavirus genome is released into the cell.

An island of ‘positive deviation 

Pavel Plevka has been living and researching in Brno for eight years. He and his wife Zuzana, who is a political scientist, have two children: five-year-old Adam and his two-year-old brother Péťa.

He has recently become the deputy director at CEITEC, which he calls an island of positive deviation. “I have to take this opportunity to put in a good word for CEITEC: one of its strengths is that the research equipment maintenance and sharing are really well organised,” he says. In particular, the more expensive items of equipment are in the central laboratories, not locked away for the use of just one researcher or team – a practice common in other Czech institutions. 

“As the deputy director, it is my responsibility to ensure the smooth operation of the central laboratories. This is key to me as a researcher, so I’m really motivated and glad that I have a say in how the labs work.” He also notes that his institution has its researchers’ back when it comes to red tape, so he is not burdened with paperwork.

“There is a lot of room for improvement in Czech academia,” he says, and it sounds a little like an understatement. “To give just one example: the practice of ‘inheriting’ research groups, which I am happy to say is not followed at CEITEC. If the research group leader leaves, so do his team. This opens up the opportunity for new group leaders and new know-how.” 

It’s gonna be big

Microscopes! This is the equipment that allows Pavel Plevka to do his job. The limitations of microscopy set the boundaries for researchers; advancements give them wings.

“Back when we discovered our ‘Pac-Man’, we studied viruses in test tubes and tried to emulate the environment that the virus is exposed to when it infects the cell. As microscopes get better and better, we can now study the virus behaviour directly in the cells. We can literally observe them as they enter the cells and start multiplying, which is fascinating to watch,” he says. 

This close-up look at the viruses enabled them to describe a new phenomenon – or rather an old phenomenon that has never been previously described.

In a nutshell: a virus can only cause an infection if it can bind to the surface of a cell and then deliver its viral genome inside the cell. Picornaviruses activate a signalling pathway, which gives the cell the sign to absorb the virus. There is one more obstacle to be overcome, though: within the cell, the viruses are enclosed in membrane sacs called endosomes. It was assumed that picornaviruses somehow create a pore in the membrane that allows the viral particles or genomes to get out and into the cell cytoplasm. 

“We were able to show that picornaviruses are indeed enclosed in endosome sacs when they enter the cell, but once inside, they induce another signal that makes the cell tear these membrane sacs apart, allowing the viral particle to get into the cytoplasm. This is when the viral particle opens up and releases its genome using the mechanism we described previously.” 

The Pac-Man-like mouth of the viral particle splits open and fills the cell with its murderous viral genetic information. The process of infection has started.

Pavel Plevka is proud of his “Pac-Man” discovery, which was well-received by other researchers in the field. However, once the latest observations of his team are published, they could cause an even bigger bang than the previous “fizzy bomb”.

“We have to verify the results of our observations on two or three more picornaviruses and more cell lines. This will allow us to conclude that our results are valid for all picornaviruses, or at least for most of them,” says Plevka. “I think that this paper will be the best contribution to science from my lab.”

When viruses kill bacteria

However, this is not the only project that the team is working on. Among other research subjects that end up under their electron microscopes are bacteriophages, or phages for short. These are viruses that infect and kill bacteria. Pavel Plevka and his colleagues study their behaviour, focusing particularly on how they interact with Staphylococcus aureus, or the golden staph, and Pseudomonas aeruginosa, as these have become increasingly resistant to any antibiotic treatment.

Bacteria resistance to antibiotics is one of the great challenges of modern biomedicine. 

Until recently, there was a widespread belief that antibiotics were the last shot in the long war with bacteria, but that turned out to be overly optimistic. 

The development of resistance in bacteria is a result of evolution: in environments where antibiotics are present, particularly in hospitals, each new generation of bacteria favours more resistant individuals. More and more strains of bacteria now laugh in the face of our pills. The massive spread of antibiotic-resistant bacteria is a result of overuse and improper use of antibiotics in medicine and agriculture.

 

Resistance to antibiotics already makes some infections difficult to treat and there is a potential disaster in the making when there will be no effective antibiotic treatment against certain strains of bacteria.

It is no surprise then that research into alternative weapons against bacteria and new ways to get around the resistance is currently in full swing – including the resurgence of targeting bacteria with bacteriophages. 

I say resurgence because the potential use of bacteriophages in the treatment of bacterial infections had been studied before Alexander Fleming forgot his Petri dishes on his lab window and discovered an extraordinary kind of mould. Once the wonderful properties of penicillin and other antibiotics were understood, further research of phage therapy was abandoned. 

But bacteriophages are back in the game now, including at CEITEC – although Pavel Plevka would like to put a lid on any unrealistic optimism right away.

“Phages and bacteria have hundreds of millions of years of evolution under their belt. They have developed, and keep using, a vast arsenal of weapons. While the bacteria have immune systems that provide a highly sophisticated defence against bacteriophages, the phages have ways to inactivate these immune systems.” This microbial arms race complicates the potential use of phages in therapy. 

“Simply put, we are entering a world where the bacteria and the bacteriophages have a long shared history. We cannot expect to find or develop a single ‘superphage’ to fight all the bacteria there is. It is likely that in clinical practice, you will always need to obtain a sample of the relevant bacteria from the patient and run a test to see which phages work against them before applying phage therapy. If we ever get this type of therapy to work, it will probably use a wide spectrum of phages,” adds Plevka. 

It almost feels as though he delights in studying the aspects that make everything more complicated. Judge for yourself: “Bacteria – such as the staph that we have already mentioned – create biofilm growths in your body, which is very ingenious. These thin layers of bacteria adhere to the surface of tissues in the body; in this way, they can better withstand the attacks of the immune system, bacteriophages and antibiotics. Biofilms are beautiful when you observe them under the microscope,” he describes lovingly.

“They are like tiny mushrooms or clumps growing on the surface. Over time, you can clearly see how the surface is colonised by the first cells, which then divide and start forming larger structures. The bacterial cells can communicate, they have their own signalling system. They can ‘say’ to each other that their biofilm is too old and should be ‘dissolved’ so that they can start working on a new layer a little way away. In a lab, when you have it under control, it’s nice and fun.”  

Obviously, it’s much less fun when it’s happening in your throat. 

As a structural virologist, Pavel Plevka is interested primarily in the structure of bacteriophage particles. “Thanks to our wonderful microscopes, Versa 3D and Titan Krios – and the skills of our team who work with them – we can look inside the infected bacteria and can see that the phages are assembled as though the bacteria was a tiny factory and each part of the phage was completed on a dedicated line. The phage particles that we study are complex: they consist of a capsid that protects the genome and a tail that allows the phage to adhere to and infect the bacterial cell.”

Inside the infected bacteria, the capsids are assembled on the cell membrane. The completed capsids detach from the membrane and move to the centre of the cells where the phage genetic information has been copied in the meantime. 

“A special molecular drive then packs the phage DNA into the capsids. The phage tails are assembled in another part of the cell and once they attach to the phage, the process is complete,” says Plevka.

He goes on to explain that the bacteriophage particles are built from hundreds of many different types of building blocks. “The individual parts of the phages are assembled in a precisely defined process as if following a plan. Once the phage particles are ready, they initiate a series of reactions that cause the bacterial cell wall to break down. This is the end of the bacteria: it explodes and the new phages can start infecting other cells.” 

When the ocean bursts into blossom

The reach of Pavel Plevka’s research group is too wide and varied to be covered in a single interview, but one area is particularly fascinating: it takes us to the ocean surface and the ecology of our planet. 

“Just as the Brno dam becomes covered with cyanobacteria blooms each year, similar blooms sometimes cover a section of the ocean surface. We study the alga Emiliania huxleyi, which causes massive blooms covering hundreds of square kilometres that are visible on satellite images. This has an impact on many processes in the ocean including the composition and amount of available nutrients – the blooms deplete almost all the iron and nitrogen.”

The overpopulated algae attract viruses that kill them but Emiliania huxleyi and some other algae leave behind their calcite shells called coccoliths.

“These tiny discs become sediments. Do you know the White Cliffs of Dover? They are composed of algae shells. It is a staggering amount of material.”

The coccoliths of Emiliania huxleyi reflect light. When the ocean blooms, it changes colour from black to white. The concentration of algae and coccoliths influences the amount of light that is reflected from the ocean surface back to space. The higher the concentration, the more light is reflected, and less heat is absorbed by the ocean.

Emiliania huxleyi is present in 65% of the ocean surface.

“Emiliania huxleyi multiplies in the ocean until it is attacked en masse by viruses. By infecting and killing the algae, the viruses decrease its concentration in the ocean – and, as a result, increase the amount of heat absorbed by the ocean and the overall temperature of the planet,” explains Plevka. 

He goes on to add: “This implies that a higher concentration of algae could compensate for the rising concentration of carbon dioxide in the atmosphere and counter global warming.”

A lab-created strain of Emiliania huxleyi with improved resistance to viral infections could potentially increase the concentration of algae in the ocean and decrease the amount of heat absorbed by the ocean.

An ocean lighter in colour would keep the planet from warming up.

However, Pavel Plevka is quick to note that “We are not planning any experiments in nature: upsetting the natural balance of things can be very dangerous.”

What comes next? 

As we already discussed, Pavel Plevka is currently happy with his position in CEITEC. He has been engaged to help create the National Institute of Virology and Bacteriology using the funding from the National Recovery Plan, an EU programme designed to boost the economy after the downturn caused by the COVID-19 pandemic.

After eighteen months of fighting a virus, plans to create a National Institute of Virology and Bacteriology sound alarmingly similar to the plans to build a speed skating rink after the Czech speed skater Martina Sáblíková won the Olympic gold. 

Hopefully, this time around it will be a responsible use of the EU funding rather than political grandiosity.

“The money won’t be used to build new facilities: it will be distributed to selected research teams that have been focusing on viruses and bacteria. Most of the funds will be used to pay the researchers and purchase supplies and the rest will go towards new lab equipment,” explains Plevka.

How does he feel now, in his early forties and in the midst of his research career? 

“It’s been eight years since I moved to Brno. Starting a research group is a risky move, it’s a lot of responsibility. The important thing is to find good people for your team. Cryogenic electron microscopy is such a fast-evolving field that I can’t expect to find colleagues with previous experience, but I have a wonderful team of motivated, capable and smart people with great expertise in electron microscopy. It’s been a lot of worrying but it turned out all right. So right now, I’m actually quite happy.”

And is he also happy with life in general? “Yes. Zuzka, Adam and Péťa are all staying with the grandparents for a few days, so I’ve had the time and space to think about such things. And I realised that I am happy. Having children is so intense, I couldn’t have imagined that before. I used to work a little in the evenings and on weekends but that’s next to impossible now if I want to spend any time with them.”

The author is an editor of Deník N.

Translated by Jana Doleželová.