The Unseen Predator

The year is 1910, and Cholera has struck your village in India. Thousands are dead. It seems that no one is safe, but little by little, a pattern is revealed: for some reason, those that bathe in the Ganges river don’t seem to be getting sick. Something in the murky, polluted water is protecting people from the disease. Little do you know, this phenomenon will soon lead us to discover Earth’s greatest unseen predator: the phage.

The spider-robot-hybrid-organisms you see in green are attaching to and infecting their prey, which to them, appears huge: a bacterium. Photo credit:  Eye of Science

The spider-robot-hybrid-organisms you see in green are attaching to and infecting their prey, which to them, appears huge: a bacterium. Photo credit: Eye of Science

When it comes to the phage, size does matter. In fact, the phage’s small size is what makes it so successful as a predator, and the most abundant biological entity on our planet. And its prey? Bacteria. Yes, phages hunt bacteria. And they do it so efficiently that they are constantly changing the makeup of bacterial communities in every environment on earth. Like a soccer coach with a rampant case of ADHD, phages are perpetually removing bacterial “players” from the game of life, adding new ones with different stats and capabilities, even modifying the foundation upon which the game is played. Phages are nature’s grand engineers. And they’re about 2,000,000,000 times smaller than we are.

Phages (short for bacteriophages) are viruses that infect bacteria. It’s taken a long time for us to develop the tools to study these tiny predators, but in the past two decades, we have come a long way in understanding how they shape ecosystems at the smallest level. While there is still much to learn, we now know a couple important things:

1.     A specific type of phage likes a specific type of bacteria: a favorite food, if you will. People in India were protected from Cholera if they bathed in the river because the river contained phages that specifically targeted and killed Vibrio cholerae, the bacteria that causes Cholera. Because of this, phage can serve as treatments for many bacterial infections. This type of treatment, called phage therapy, is an exploding field right now, as we face resistant bacterial strains that antibiotics can no longer fight.

2.     When a phage infects a bacteria, it is faced with a decision, and this decision has huge ramifications for the bacterial community, transforming environments from the ground up.

Let’s talk a little bit more about this decision. When a phage infects a bacteria, it can do one of two things. In the first scenario, the phage turns the bacteria into a factory, using the cell’s resources to create hundreds of new phage particles. It does this because it has no organs of its own: the beautifully simple phage is just a little packet of genetic information that uses the life around it to make more of itself. After it has used the cell’s machinery, the phage breaks open the cell, killing it and releasing hundreds of new phages into the environment to continue the cycle. We call this lytic replication, and it’s what allows viruses to spread like wildfire.

Electron microscopy image of a bunch of bacteriophages (in green) attacking and lysing a bacteria (in purple). This is happening all around you, all the time. Image credit: Helmholtz Centre for Infection Research, Braunschweig, Germany) and colorized by Dwayne Roach (Institut Pasteur).

Electron microscopy image of a bunch of bacteriophages (in green) attacking and lysing a bacteria (in purple). This is happening all around you, all the time. Image credit: Helmholtz Centre for Infection Research, Braunschweig, Germany) and colorized by Dwayne Roach (Institut Pasteur).

But the phage has another choice. Instead of going lytic, the phage can integrate its DNA into the DNA of the bacteria, acting as a hitchhiker in the bacterial cell and allowing it to replicate with the bacteria. This means it is passed on to all future generations. We call this the lysogenic cycle. The phage that is hitching a ride, which we now call a prophage, often carries genes that make the bacteria stronger or more likely to survive, such as giving it antibiotic resistance, tolerance to extreme environmental conditions, or preventing other viruses from infecting it.

By arming the bacteria with helpful traits (think Ironman’s suit of armor), the phage ensures its own survival. And down the line, if the bacterial cell is threatened, the phage can “pop out” of the bacterial DNA and begin the lytic cycle anew, creating more of itself and killing the cell.

So how does a phage make the decision between going lytic and killing its host, or hitching a ride and staying for a while? To answer this, we have to think like a predator.

The way viruses go about hunting their prey is eerily similar to how macro-scale predators do: by minimizing the energy used to hunt, and using strategy. Photo credit: Avel Chuklanov

The way viruses go about hunting their prey is eerily similar to how macro-scale predators do: by minimizing the energy used to hunt, and using strategy. Photo credit: Avel Chuklanov

When there’s a lot of bacteria around, we expect the phage to go through more lytic replication, because there is more prey for them to infect (picture the smile on a solitary lion in a field full of gazelle). We call this Kill-the-Winner dynamics, because we expect phage to attack and kill the faster-growing or more successful bacteria. For the past several decades this theory has shaped our understanding of predator-prey dynamics among phage and bacteria. In this way, phage control the amount of bacteria present in an ecosystem, and by killing off the successful ones, encourage huge diversity in bacterial populations and keep bacteria in check.

Similarly, when bacteria are scarce, the phage tend to hitchhike more, hedging their bets inside the safety of the bacterial cell until conditions get better and they can find more prey. We call this Piggyback-the-Loser dynamics, where phage will integrate themselves into any bacteria and give them helpful traits in order to stay alive.

But the plot thickens. We measure these dynamics by looking at the ratio of viruses to bacteria in an ecosystem, or VMR (virus to microbe ratio): if there are more phages present, chances are they are using lytic growth, and if there are less phage present, they are probably hiding away in the cells as prophages. Recently, one group of scientists at San Diego State University noticed that as bacterial populations grew large enough, the ratio of phages to bacteria actually decreased; the opposite of what they were expecting! This phenomenon has been confirmed in many different environments around the globe: as the prey gets abundant enough, the predators stop ‘predating’ as much.

In this graph by the  authors , it is clear that in all ecosystems, VMR is lower at lower microbial abundances (Piggyback-the-Loser, higher at moderate abundances (Kill-the-Winner), and low at high abundances (Piggyback-the-Winner).

In this graph by the authors, it is clear that in all ecosystems, VMR is lower at lower microbial abundances (Piggyback-the-Loser, higher at moderate abundances (Kill-the-Winner), and low at high abundances (Piggyback-the-Winner).

A third hypothesis was coined to explain this phenomenon, called Piggyback-the-Winner, in which phage integrate more into bacterial DNA when bacterial populations get high enough. We think they do this out of, for lack of a better term, laziness: when bacteria are replicating quickly and reaching high abundances, the phage don’t need to devote energy to making more of themselves or compete with other phages, they just piggyback on the microbes’ success. Another expert strategy by a mind-bendingly intelligent parasite.  

As we understand it now, the number of bacteria in an ecosystem is what determines whether we see Piggyback-the-Loser, Kill-the-Winner, or Piggyback-the-Winner dynamics in phage. This switch between lytic and lysogenic life cycles – when, why and how they do it – is still mysterious, and warrants further investigation. But in global environments, the strategy they use does matter. 

On a degrading coral reef, for example, we see a massive spike in bacterial populations, which thrive in the nutrient-rich waters. If phages are staying cooped up in their bacteria, giving them new traits and new capabilities instead of targeting and killing them, this could be making the situation worse. On the other hand, considering we know bacteria are one of the driving forces behind coral reef decline, looking to their predators may someday offer a solution to helping global coral ecosystems recover.

Changing microbial community dynamics on reefs are likely one of the driving forces behind global coral reef degradation. Photo credit: Jeremy Bishop

Changing microbial community dynamics on reefs are likely one of the driving forces behind global coral reef degradation. Photo credit: Jeremy Bishop

At the end of the day, we can’t offer much help to any ecosystem unless we understand the forces that are shaping it at the smallest level. Phages, although unheard and unseen, represent one of the last great frontiers that human knowledge has yet to breach. Who knows what unraveling the secrets of the planet’s smallest hunter could teach us about the world, and ourselves?

-Jason


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