T4 bacteriophage. Image by Frederick A. Eiserling/UCLA and Petr Leiman/Purdue Department of Biological Sciences. Source
T4 bacteriophage. Image by Frederick A. Eiserling/UCLA and Petr Leiman/Purdue Department of Biological Sciences. Source

Meet Your New Symbionts: Trillions of Viruses

With deadly new viruses emerging these days in Saudi Arabia and China, it can be hard to imagine that viruses can be good for anything. It’s easy to forget that we are home to trillions–perhaps quadrillions–of viruses on our healthiest days. And, according to a team of California scientists, those viruses are our symbiotic partners, creating a second immune system. These viruses serve as a defensive front-line, keeping bacteria from invading our gut lining and causing deadly infections.

The viruses in question are far less familiar than, say, influenza viruses or Ebola viruses. They are known as bacteriophages, which means “eater of bacteria.” And yet bacteriophages (or phages for short) are vastly more common than viruses that infect humans. They’re more common than all the viruses that infect every animal on Earth. The reason is simple arithmetic: there are far more hosts for phages to multiply in than there are for viruses that infect our own cells. They’re in the ground, in the oceans, under ice, and in the air. By some estimates, there are 1031 phages on Earth. That makes phages the most abundant life form, period.

Despite the fact that phages are just about everywhere, it was inside of humans that scientists first discovered them. Felix d’Herelle, one of the co-discoverers, came across them while treating French soldiers in World War I. He filtered the stool of soldiers sick with dysentery and isolated microscopic particles that could kill the dysentery-causing bacteria. The idea that bacteria had viruses seemed far-fetched to d’Herelle’s fellow scientists, and it wasn’t until the 1930s that engineers developed microscopes powerful enough to see them, to document their attacks on bacteria. d’Herrelle spent the rest of his life trying to transform phages into a medical weapon against bacterial infections. “Phage therapy,” as his method came to be known, continues to attract curious scientists over sixty years after his death. While it’s not ready to replace antibiotics, phage therapy is starting to be used to disinfect food.

For scientists who pursue phage therapy, phages are simply weapons to be deployed in a medical battle. By comparison, we don’t know much about these phages in nature–in other words, on what phages do in our inner ecosystem. It has been, frankly, too hard of a problem. If you’re an ecologist studying how lions control their prey’s populations, you can go out to a savanna and watch lions. You can tag lions. You can scoop up lion scat. Viruses that live inside our bodies–that don’t even make us sick–are practically invisible to science.

That’s starting to change. In recent years, our inner world of microbes has become the subject of massive scientific research. (Michael Pollan has a long feature on the so-called microbiome in this week’s New York Times Magazine; here’s an article of mine from last year’s New York Times.)

Scientists who study the microbiome have focused most of their efforts on mapping the diversity of the 100 trillion bacteria in our bodies. Part of the reason is practical. To conduct these surveys, scientists take samples–skin scrapings, saliva, stool, and so on–and strip away everything except the fragments of DNA in them. Then the scientists sequence those fragments and identify their origins. Bacteria, which generally have much larger genomes than viruses, are much easier to recognize this way.

This research has revealed a world of vast complexity–and a world on which our own well-being depends. Our resident bacteria break down tough plant matter, synthesize vitamins, and keep invading pathogens from taking over our bodies.

But that doesn’t mean that our bodies embrace the microbiome without reserve. As we get to know the microbiome better, we shouldn’t fool ourselves into thinking of it as some wise guardian angel. It’s a horde of several hundred species of microbes, a horde that can do some stupid things.

Consider the bacteria that line the delicate walls of our large intestines. If they multiplied with abandon, they would end up pushing down into the intestinal wall, pressing against our cells and wedging between them. If they broke through, they’d get swept away into the bloodstream where they could cause dangerous infections.

Our intestinal walls are also loaded with immune cells, and they can make this kind of a breach even more damaging. They may overreact, causing dangerous levels of inflammation in the intestines–creating a new environment that can foster the growth of disease-causing bacteria.

To avoid this disaster, our bodies hold back the microbiome. One strategy that intestinal cells use for their defense is secreting a dense layer of mucus.  While the surface of the mucus provides lots of tasty food for bacteria, the lower levels are so dense they’re hard for the microbes to invade. Our intestines also defense themselves from the microbiome by secreting microbe-killing molecules to knock off any bacteria that get too close to breaching the wall. And when pathogens invade, our intestines can ramp up these defenses–making more antimicrobials and even thicker layers of mucus.

But these defenses are no guarantee of safety. Indeed, some pathogens have actually evolved the ability to hack our defenses for their own benefit. Salmonella, for example, goes out of its way to trigger inflammation in the gut. In the toxic environment created by the immune system, Salmonella outcompetes other bacteria. And as immune cells move into the intestinal lining to attack, Salmonella performs its greatest humiliation: it invades the very immune cells that are supposed to protect us.

If we focus only on the relationship between human cells and bacteria, however, we miss a third major player in our intestinal ecosystem. Phages thrive in our guts, attacking bacteria and using them to make more copies of themselves.

Phages tend to specialize on certain strains of bacteria. To invade a host microbe, they act like a thief using a key to slip into a locked house. Proteins on a phage’s surface bind to proteins on a host cell, creating a passageway through which the phage can inject its genes. This video below shows what it looks like when a phage called T4 invades E. coli:

This intimate relationship between phages and their victims turns them into coevolutionary partners. A mutation that alters a microbe’s lock will be favored by natural selection, because it makes the phage’s key less effective. (The  mutation has to be able to bring about this change without harming the microbe itself.) The phages, in turn, benefit from mutations that adapt their keys to the new locks.

These arms races may also help explain the tremendous diversity of microbes in our guts. When one strain of bacteria has a population boom, it creates lots of new opportunities for its phages to multiply as well. Eventually, the phages may become so abundant that they decimate their host population. That crash may let another strain of bacteria rise up and become dominant–only to be driven down by its phages.

But what if there was a hidden partnership between phages and us? What if the enemy of our frenemy was our friend?

Jeremy Barr of San Diego State University and his colleagues recently explored this possibility in a study they’re publishing this week in the Proceeding of the National Academies of Sciences. They started their investigation with a simple but profound observation: compared to other parts of the intestines, the mucus layer is packed with phages.

This might simply be a matter of predators going to where their prey are. But when Barr and his colleagues took a closer look, they found evidence that our own bodies make the mucus layer an inviting home for the phages.

Some of this evidence comes in the form of hooks that grow on the phages. To understand what their function was, the scientists engineered phages that didn’t make the hooks. They did no worse at invading bacteria in a Petri dish. So the hooks are not involved in infection, like their keys. The hooks must therefore have another function.

Barr and his colleagues carried out a series of experiments to find out what that function was. The answer lies not with bacteria, but with us. The hooks are exquisitely adapted to latching on to certain molecules that make up our mucus, known as mucin glycoproteins. Thanks to their hooks, phages drifting through our intestines can snag onto the mucus, forming a viral carpet.

To see what sort of effect that carpet had, Barr and his colleagues ran another set of experiments. They created two cultures of human cells. In one culture, the cell grew in a layer and produced a covering of mucus. In the other culture, the cells produced no mucus.

Then the scientists sowed phages on all the cell cultures. They gave the phages some time to anchor themselves, and then washed away any phages that were still floating free. Finally, the scientists added bacteria on top of the cultures and let them grow for four hours.

The differences between the two cultures were stark.The normal cells snagged an abundance of phages in their mucus layer, and the viruses killed off most of the bacteria. The cells that couldn’t make mucus, on the other hand, ended up with no phages to defend them. The bacterial population exploded, killing off some of the human cells underneath.

What makes this discovery all the more fascinating is how the phages hook onto mucin glycoproteins. At first glance, those would seem like the worst target a virus could go after. There is no single kind of mucin glycoprotein in your body. Scientists have identified 19 kinds, and there may be many more. The variety comes from how we make them. First, our cells make a protein; then they decorate it with sugars in many different patterns. A hook that lets a phage grab onto one glycoprotein will be useless for another.

Phages seem to be equipped to handle this variety. It turns out that the gene for the phage hook is far more prone to mutating than its other genes. Each time a phage produces new viruses, they generate new shapes to fit different mucin glycoproteins.

All this suggests that the phages in our guts have evolved a sophisticated strategy for taking hold in the mucus layer of the gut. It allows them to find an abundant supply of victims to kill. It may be a winning strategy for us to, because the phages become an extra immune system for our own bodies. Bacteria settle onto the top of the mucus layer, feed, and grow. But as they spread down towards the wall of the intestines, they encounter a dense barrier of phages. The phages kill them off and increase their numbers even more, creating an even more powerful barrier of defense.

Scientists have found viruses in other species, such as fungi, plants, and insects, that help out their hosts. It’s possible that we can add ourselves to the list of hosts that depend on their own virome. If this new research holds up, it will be fascinating to see how far evolution has taken this partnership. Many species that host symbiotic microbes go to great lengths to care for their residents. Some insects even grow special organs to house them. Do we tailor our intestines to grow as many phages as possible?

Answers to these questions might eventually provide us with a new way to approach the enduring dream of phage therapy. Rather than unleashing an invasion of shock troops on infections, maybe we should learn how to help our phages keep up their quiet defenses.

(For more on bacteriophages, see my book A Planet of Viruses.)