To kill or not to kill

Understanding their behavior could help in the search for alternatives to antibiotics, says Prof TAU

Viruses, bacteria and other microorganisms are more like humans in their behavior than we imagine, researchers have found. They make informed decisions, they interact socially, and they will choose to compete or cooperate, depending on what suits their interests. They can help or harm each other to ensure their own survival. And they can kill or lie dormant, depending on the circumstances. This is sophisticated behavior for a 0.0001 mm microbe.

“Over the past 15 to 20 years, it has become clear that bacteria and more recently some viruses can be considered to have social interactions,” Professor Avigdor Eldar of Tel Aviv University 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.

Prof. Avigdor Eldar, of Tel Aviv University Credit TAU

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

In a study published in December 2021 in Natural microbiologyEldar and his team of researchers from the Shmunis School of Biomedicine and Cancer Research have uncovered new complexities in social biology – namely the communication and decision-making process of phages viruses, which are harmless to humans but are the natural enemies of bacteria.

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

“When [the virus] kills 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 they can infect and then kill, they can spread much faster. On the other hand, if there’s not a lot of bacteria available, it’s better [become dormant and] stay in the bacteria. Since the bacterium replicates, it’s actually pretty good that the virus just stays in the bacterium and replicates with it.

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

How does it know if there are free prey to infect? By communicating with loved ones. “When the virus enters the cell, it produces a [chemical] signal, then sends it out of the cells. [Simultaneously], it produces a specific receptor that can detect that chemical. So the logic is that if the virus “smells” a lot of itself, then if it smells [a lot of] these signaling chemicals, it will not try to infect but will become dormant,” he says.

Research on the first step in the decision to kill or become dormant had predated the present study, and the results were published by colleagues at Eldar in 2017. What remained to be clarified was how phages decide – after choosing the dormant state – when to wake up. to rise, kill the host and spread, and when to go dormant, notes Eldar.

Abandon the sinking ship

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

At the same time, there is also signaling gathered from surrounding phages that determines if there will be any available spots after abandoning ship. In fact, even when dormant, the virus hasn’t stopped producing and capturing chemical signals, Eldar says.

Bacteria attacked: The cells that harbor the virus turn from blue to yellow. TAU credit

“Our article showed 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] signage. So basically the virus has two questions: First, is my ship damaged? Second, do I see other undamaged and unoccupied places around me? If it “senses” that it is surrounded by many other phages, it will not kill the bacterium but will let it try to correct its own DNA. Basically, there is no reason to leave the sinking ship unless you know there is a safe haven somewhere. Otherwise, it’s better to try and let the sailors fix it,” he said.

love-hate relationship

“These viruses have a sort of love-hate relationship with bacteria,” Eldar continues. “When they’re dormant, they actually want the bacteria to thrive, because when the bacteria thrives, the virus also benefits, because it can grow and replicate with the bacteria. Sometimes the virus [actively] help the bacteria. Thus, it brings really useful genes to the bacterium, either to protect itself 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 could examine how bacteria could potentially exploit weaknesses in the virus’ chemical signaling system. “You could hypothesize 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 bacteria.

Microscopic viruses attack host bacteria. . . and the bacteria defend themselves. Credit Deposit Photos

“Now, if the bacterium was able to [replicate] this signal, the virus will assume that the signal is emitted by another virus [of its kind]. So it can trick the virus into thinking that there are a lot of other viruses around and it won’t kill the bacteria, but just go to its dormant state,” he muses.

“So it’s an interesting compromise that, whenever there is information that is made [and consumed]there is a [opportunity] for handling. »

Future prospects: killer viruses in medicine

The destructive properties of phage viruses can also be used in medicine to eliminate harmful bacteria from the human body, Eldar explains. “So there’s this area, which has actually gained traction in recent years, called ‘phage therapy’, and it works as a sort of alternative to antibiotics. Usually this field uses viruses that can only kill bacteria, because they actually want to kill bacteria, they don’t want them to go dormant,” he says.

The research he and his colleagues are doing on virus decision-making could be helpful here. “Usually, [these viruses] are very fast, because they don’t have to decide, they go in immediately and kill. However, it has been shown in the past that these types of viruses too, under certain conditions, will have to make decisions. [For instance], when they infect the bacterium, they can decide to kill it quickly and less efficiently, or more slowly and more efficiently. Because, again, under certain conditions, it’s better to be quick and dirty and then go and infect others. [But] if there is very little prey in the environment, it is better to be slower and more efficient in how you kill bacteria.

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

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