The Infection Heist: How Social Viruses Team Up for the Perfect Score

virus bank heist
The safe-cracker, the inside man, the getaway driver. Each member plays a key role in a bank heist. This metaphor helps explain how different viruses interact to co-infect cells. David Slipher/(CC0)

If you’ve seen any heist movie, you know it takes a team to get the job done. The safe-cracker, the inside man, the getaway driver. Each member plays a key role, without which the group’s success is jeopardized.

Viruses in a competitive environment work in a similar way. A perspective paper published in mSystems suggests that interactions between viruses are more complicated than virologists originally thought. Using social evolution theory, Samuel Díaz-Muñoz, assistant professor of microbiology and molecular genetics, hopes to help fight viral and bacterial infections with new treatments that harness interactions between viruses.

Díaz-Muñoz sees understanding the social interactions of viruses as a key to help limit viral outbreaks. With fellow researchers Rafael Sanjuán of the University of Valencia and Stuart West of Oxford University, he has coined the term “sociovirology” which aims to develop evolutionary models to help predict virus-virus interactions. Similar models have been developed for bacteria, cancer and many other levels of biology.

“We have a new lens to look at viruses that might change some fundamental principles of virology and definitely bring new approaches to treat bacterial and viral diseases,” said Díaz-Muñoz.

It’s always better when we’re together

H1N1 virus under microscope
An electron micrograph reveals 1918 H1N1 influenza strain virus particles (in green) attacking a cell (in blue). NIH/NIAID

Successful virus strains can team up to accomplish their objective of infecting a host cell. One virus strain might have a specialized, lock-pick like protein which is particularly effective at cracking the cell’s vault. 

A second virus strain excels at the getaway, exiting the cell and evading antibodies that might pursue it. Together, the two viruses succeed in co-infecting the cell and divvying up the ultimate score—their individual reproductive successes.

But as with most good heist scenarios, circumstances change. Cooperation between the team may end once a role is fulfilled. Take out one of the strains and suddenly there’s one less member with which to split the loot. For a virus, it’s always about looking out for yourself ahead of the competition.

“Social interaction isn't always collaborative,” said Díaz-Muñoz. “It can be neutral and it can be detrimental to different extents. When the situation changes, the relationships change.”

In the lab, Díaz-Muñoz creates viral environments with different levels of competition to test his theory. In one scenario a virus, called strain A, is all alone. In other scenarios, it’s partnered with a different strain, strain B, or many strains CDEFG, etc., in a competitive environment.

“We're not looking at only strains A and B. We're trying to look at ABCDEFG down the line and their combinations,” Díaz-Muñoz said. “And so that is why it becomes incredibly complex.”

How does Strain A perform in these different scenarios and how do these actions affect the offspring it generates? Predicting the outcomes becomes extremely difficult as more and more variables are added. But denser environments increase the likelihood among different parental strains for interaction—be it cooperation, cheating or something in between.

virus microscopy
Systems like game theory can help create theoretical models for virus-virus interactions. CDC

 

What does it mean to be social?

While the bank heist scenario illustrates a fun, anthropomorphic overreach, Díaz-Muñoz is quick to point out that social activity doesn’t imply that viruses act with intentional decision making or even conscious awareness.

“You don't need to be sophisticated at all to be social,” said Díaz-Muñoz. “It's not that they know what they’re doing, it's just that the behavior happens to be advantageous in that setting.”

For virologists, being social simply means that one virus affects the reproduction of another. There’s no learning per se, only reactions. Successful reactions promote survival, while unsuccessful attempts could mean doom.

In crowded environments, viruses can “cheat” competing strains out of their reproduction. Coinfection of a cell results in multiple infecting viruses, called parents, combining the genetic material they’ll pass on, much like human parents each contributing an equal part of their genetic code. But cheater viruses have techniques to bias this process to favor their progeny.

The complexity of co-reproduction means that offspring strains could include a mish-mash of all parents’ DNA, and if there are cheaters at work, the researchers will be able to spot them by analyzing the genome segments of the offspring strains. Does a segment show preference for promoting one strain at the expense of the other?

virus illustration
This digital illustration shows a cell infected with a generic influenza virus. The viral envelope in tan protects the virus' genetic material from a host's immune cells, and the proteins in blue and red help recognize and bind to a host's cells. CDC

The viral strains the Díaz-Muñoz Lab studies include those responsible for the 1968 and 2009 influenza pandemics, among other epidemic strains. Researchers like to pick these popular strains because their infection rates are well characterized. Together, they represent a diversity of genetic variation and separation in time and geography which makes them valuable models.

Gaming the system

While viruses aren’t active decision makers and only perform a specific task to exploit an advantage, Díaz-Muñoz uses systems like game theory to help explain scenarios of cooperation and competition.

One example is that of the Prisoner’s Dilemma. In this scenario two criminals are imprisoned separately. The authorities don’t have enough evidence to convict them both so each prisoner is given the opportunity to either cooperate and betray his partner, or remain silent to protect each other. It’s a classic example of how two individuals may not cooperate, even if doing so is actually in their best interest.

Scenarios like this bring elements of game theory into the virology mix, with applications in logic and computer science, mathematics, and social sciences. This theory has been tested in viruses by Paul Turner (Yale University) and Lin Çhao (University of California, San Diego). Díaz-Muñoz aims to extend the work of his postdoctoral advisors beyond the lab, to see if similar dynamics play out in natural viral infections.

Díaz-Muñoz will continue to expand the variety and complexity of his virus environments, eventually introducing combinations of 3-4 parental virus strains to evaluate their social behavior.

Sociovirology is shaking down the long-held assumptions of virology, as co-infection can change every stage of the viral lifecycle and can provide better models for how viruses interact in natural environment. Díaz-Muñoz envisions that this emerging field may rewrite the textbook doctrines of how viruses function at the most fundamental level.

 “It turns out viruses have been dealing with each other for millions of generations. Maybe we can learn something from them in our own battles with viral diseases,” said Díaz-Muñoz.

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