To Kill Or Not To Kill – How Viruses Make Informed Decisions

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

Viruses, bacteria and other micro-organisms are more like humans in their behavior than we’d imagine, researchers have found. They make informed decisions, they interact socially, and they will choose to either compete or cooperate, depending on what suits their interests. They can assist each or undermine each other to ensure their own survival. And they can kill, or remain dormant, depending on circumstances. It’s sophisticated behavior for a 0.0001 mm microbe.

“In the last 15 to 20 years, it became evident that bacteria and more recently some viruses can be thought to have social interactions,” Professor Avigdor Eldar from Tel Aviv University tells 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 choice in situations among 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 Microbiology, Eldar and his team of researchers  at the Shmunis School of Biomedicine and Cancer Research uncovered new complexities in social biology – namely the communication and decision-making process of the phage virus, which are harmless to people but are the natural enemies of bacteria.

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

“When [the virus] kills the bacteria, it can produce something like, let’s say, 50 to 100 copies of itself,”says Eldar. “So, if there are many bacteria around, which it can infect, and then kill, it can spread much more rapidly. On the other hand, if there aren’t many available bacteria around, it’s better to [become dormant and] stay in the bacterium. Since the bacterium replicates itself, it’s actually pretty good for the virus to just stay within the bacterium and be replicated with it.” 

He adds that availability of bacteria is determined by the level of infection. In fact, bacteria can be claimed by one phage virus at a time, meaning that a virus will have to ensure surrounding bacteria are not occupied by their peers. 

How does it know whether there is free prey around to infect? By communicating with its kin. “When the virus goes into 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 signalling chemicals, it will not try to infect but will become dormant,” he says. 

Research on the first-stage decision to kill or become dormant had preceded the present study, and the results were published by colleagues of Eldar in 2017. What remained to be clarified was how phages decided – after having chosen the dormant state – when to wake up, kill the host and spread, and when to stay dormant, notes Eldar.

Abandoning the sinking ship

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

At the same time, there is also the signalling collected from the surrounding phages that determines whether there will be available spots following abandoning of ship. In fact, even when dormant the virus has not stopped producing and capturing chemical signals, says Eldar. 

“Our paper has shown that the virus makes a more complicated decision [when awakening than when going to sleep]. The virus needs to combine the two pieces of information together, both the damage [of the bacteria] and the [surrounding] signaling. So, basically, the virus asks itself two questions: first, is my ship damaged? Second, do I see other non-damaged and non-occupied places around me? If it “smells” that it is surrounded by many other phages, it will not kill the bacteria but let it try correcting its own DNA. Basically, there’s a reason to leave the sinking ship only if you know that there’s a safe haven somewhere. Otherwise, it’s better to try and actually let the sailors repair it,” he says.

Love-hate relationship

“These viruses have a kind of a love-hate relationship with the bacteria,” continues Eldar. “When they are dormant, they actually want the bacterium to prosper, because when the bacterium prospers then the virus will also profit, because it can grow and replicate with the bacterium. Sometimes the virus [actively] helps the bacterium. So, it brings genes that are actually helpful for the bacterium, either to protect against other viruses or [against] antibiotics.”

That being said, bacteria are not passive victims and they have their own ways of manipulating the virus. According to Eldar, future research may look into how bacteria could potentially exploit weaknesses in the virus’ chemical signalling system. “You could hypothesise that the bacterium can [in turn] manipulate the virus. In a sense, this mode of communication of the virus is also [its] Achilles’ heel. If you think about it, the virus is now inside the bacterium.

“Now, if the bacterium were able to [replicate] this signal, the virus will assume that the signal is being 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 bacterium, but just go to its dormant state,” he muses. 

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

Looking ahead: killer viruses in medicine

The killing properties of phage viruses can also be used in medicine to remove nefarious bacteria in the human body, says Eldar. “So there’s this field, which has been actually gaining some traction in recent years, which is called “phage therapy,” and it works as a kind of alternative to antibiotics. Usually, this field uses viruses which can only kill the bacteria, because they actually want to kill the bacteria, they don’t want it to become dormant,” he says.

The research he and his colleagues are doing on virus decision-making could come-in handy here. “Usually, [these viruses] are very quick, because they don’t have to decide, they immediately go in and kill. However, it was shown in the past that these kinds of viruses as well, under some conditions, will have to make decisions. [For instance], when they infect the bacteria, they can decide to kill it quickly and less effectively, or more slowly and more effectively. Because, again, under some conditions, it is better to be quick and dirty and then go and infect others. [But] if there is very little prey in the environment, it’s better to be actually slower, and more efficient in the way you kill the bacteria.” 

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

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