To kill or not to kill – How viruses make informed decisions

Understanding their behavior could help search for alternatives to antibiotics, says TAU prof

Viruses, bacteria and other microorganisms are more similar in behavior to humans than we might suspect, researchers have discovered. They make informed decisions, they interact socially, and they will choose to compete or collaborate depending on what suits their interests. They can help or undermine each other to ensure their own survival. And they can kill or remain dormant, depending on the circumstances. It’s advanced behavior for a 0.0001 mm microbe.

“Over the past 15 to 20 years, it became clear that bacteria and more recently some viruses have social interactions,” Tel Aviv University professor Avigdor Eldar told NoCamels. “And [just like with humans], in these social interactions you see a lot of competition. You see cooperation, you see conflict, you see manipulation, [and] you also see eavesdropping.”

Economists would call this game theory – a framework for understanding choices in situations between competing players. Scientists discussing non-human organisms prefer to call it “social biology,” but the rules are similar.

In a study published in December 2021 in Nature MicrobiologyEldar and his team of researchers at the Shmunis School of Biomedicine and Cancer Research discovered new complexities in social biology, namely the communication and decision-making process of the phage virus, which are harmless to humans, but are the natural enemies of bacteria.

Phage viruses try to reproduce themselves as much as possible. To do this, they infect a single bacterium and use it for their multiplication purposes. Once inside a bacterium, the virus must first make one of two possible decisions: kill the host immediately, or remain “dormant” and kill it later.

“When [the virus] kills the bacteria, it can produce something like, say, 50 to 100 copies of itself,” says Eldar. “So if there’s a lot of bacteria around that it can infect and then kill, it can spread much faster. On the other hand, if there are not many available bacteria around, it is better to [become dormant and] remain in the bacteria. Because the bacteria replicates itself, it’s actually pretty good for the virus to just stay in the bacteria and be replicated with it.”

He adds that the availability of bacteria is determined by the degree of infection. Bacteria can in fact be claimed by one phage virus at a time, which means that a virus must ensure that surrounding bacteria are not ingested by their congeners.

How does it know if there is free prey nearby to infect? By communicating with his relatives. “When the virus enters the cell, it produces a [chemical] signal and then sends it out of the cells. [Simultaneously], it produces a specific receptor that can sense this chemical. So the logic is that if the virus “smells” a lot of itself, so if it smells [a lot of] these signaling substances, it will not try to infect, but will become inactive,” he says.

Research into the first-stage decision to kill or go dormant preceded the current study and the results were: published by colleagues from Eldar in 2017. What remained to be elucidated was how phages decided — after choosing the dormant state — when to wake up, kill the host and proliferate, and when to remain dormant, Eldar notes. on.

Leaving the Sinking Ship

“Normally most viruses make the decision [to wake up] when there is damage to the cell, usually DNA damage. It’s like leaving a sinking ship,” he says.

At the same time, there is also the signaling collected from the surrounding phages that determines whether there are available spots after leaving the ship. Even when the virus is dormant, it hasn’t even stopped producing and recording chemical signals, Eldar says.

“Our paper has shown that the virus makes a more complicated decision [when awakening than when going to sleep]† The virus must combine the two pieces of information, both the damage [of the bacteria] and the [surrounding] signalling. So basically the virus asks itself two questions: First, is my ship damaged? Second, do I see other undamaged and unoccupied places around me? If it “smells” that it is surrounded by many other phages, it will not kill the bacteria, but let it try to correct its own DNA. In short, there is only a reason to abandon the sinking ship if you know that there is a safe harbor somewhere. Otherwise, it’s better to try and let the sailors really fix it,” he says.

Love-hate relationship

“These viruses have a kind of love-hate relationship with the bacteria,” Eldar continues. “If they’re inactive, they actually want the bacteria to thrive, because if the bacteria thrives, the virus also benefits, because it can grow and multiply with the bacteria. Sometimes the virus [actively] helps the bacteria. So it brings with it genes that are really useful for the bacterium, either to protect against other viruses or to [against] antibiotics.”

That said, bacteria are not passive victims and they have their own ways of manipulating the virus. According to Eldar, future research could explore how bacteria could potentially exploit weaknesses in the virus’s chemical signaling system. “You could assume that the bacterium can [in turn] manipulate the virus. In a sense, this way of communicating the virus is also: [its] Achilles heel. If you think about it, the virus is now in the bacteria.

“If the bacteria could do that… [replicate] this signal, the virus will assume that the signal is made by another virus [of its kind]† It can therefore make the virus think that there are many other viruses around and it will not kill the bacteria, but just go into its dormant state,” he muses.

“So it’s an interesting trade-off that, when information is being made… [and consumed]there is a [opportunity] for manipulation.”

Looking ahead: deadly viruses in medicine

The killing properties of phage viruses could also be used in medicine to get rid of nefarious bacteria in the human body, Eldar says. “So there’s an area that’s really gaining popularity in the last few years that’s called ‘phage therapy’, and it’s working as sort of an alternative to antibiotics. Most of the time, this field uses viruses that can only kill the bacteria because they actually kill the bacteria.” want to kill, they don’t want it to become inactive,” he says.

The research he and his colleagues are doing on virus decision-making can help with this. “Usual, [these viruses] are very fast, because they don’t have to decide, they go right in and kill. However, it has been shown in the past that these types of viruses will also have to make decisions under certain conditions. [For instance]When they infect the bacteria, they may decide to kill it quickly and less effectively, or more slowly and more effectively. Because again, under some circumstances it is better to be fast and dirty and then start infecting others. [But] if there’s very little prey in the environment, it’s better to be really slower, and more efficient in the way you kill the bacteria.”

“So [our research on phage decision-making] may affect our understanding of the [ways] these highly aggressive viruses [operate]† Because they will also have to communicate [with their peers] to make the [above] decisions.”