The Berkeley Science Review: Articles

Battle of the Bugs
The evolution of bacterial immunity (view PDF)
by Katie Berry

It is war. Every two weeks, half of the population is destroyed. The survivors adapt to outsmart the enemy, but the enemy quickly evolves its strategy and will continue to kill. This is the largest arms race on the planet: the epic battle between bacteria and the viruses that infect them. Scientists have long known that bacteria can be infected by viruses called bacteriophage (from the Greek for "bacteria-eaters"). There can be no quarter in the conflict between these foes, as the phage cannot reproduce without infecting the bacteria, while the bacteria will not survive to propagate if the phage infection is successful. "It really is a tug-of-war," explains Blake Wiedenheft, a postdoctoral fellow in Jennifer Doudna's laboratory in the Department of Molecular and Cellular Biology. "That's what evolution is. The bug responds and then the virus responds in kind, as a consequence of that selective pressure."

Scientists had believed that bacteria evade viral pathogens primarily by systematically eliminating any foreign DNA that they find inside of themselves, which is often injected by viruses. Recent findings over the past four years, however, suggest that bacteria are capable of much more complex approaches to warding off viral invaders. "What we're beginning to realize," says Wiedenheft, "is that bacteria have an immune system that adapts to viruses. It will recognize those viruses, and it will be prepared to defend itself against them." This notion of adaptive immunity is conceptually very similar to the way the human immune system works. Once we've been exposed to a particular pathogen, either by a vaccination or by prior infection, we are much less likely to be infected a second time. Our bodies remember the infectious agents that have previously been encountered and maintain an arsenal of countermeasures against them, like antibodies, proteins that bind to these invaders and target them for destruction.

Despite this similarity to human adaptive immunity, the newly discovered bacterial immune system has a completely different mechanism. It is based on nucleic acids and is centered around a region of the bacterial chromosome that goes by the descriptive acronym CRISPR: clusters of regularly interspaced short palindromic repeats. These repetitive sequences were noticed in the DNA of many bacteria when their genomes began to be sequenced twenty years ago, but nobody was sure of their purpose. It was only four years ago that researchers recognized with excitement that the "spacer" sequences in between the repetitive elements actually match sequences from the genomes of viruses that infect the bacteria.

It appears that when bacteria recognize the DNA of an invading virus, they cut it up and incorporate a short piece of the virus' genetic material into their CRISPR region between the repetitive sequences. Exactly how this leads to immunity is still a subject of active research. Recent reports suggest some similarity to the mechanism of RNA interference (RNAi) in higher organisms. It seems that bacteria make RNA from the DNA of the CRISPR region, which is then diced into small pieces that are hypothesized to interfere with either the DNA genome or the messenger RNA of an invading virus through the same sort of base-pairing interactions that stitch together the double helix of DNA. While the mechanism of CRISPR-based immunity still remains hazy, what is clear is that the next time the bacterium encounters that virus, "it uses the information it just acquired from the parasite to target that parasite to kill it," explains Wiedenheft. Essentially, it's a flu shot for bacteria.

The realization that microorganisms show such sophistication in their defense against viral parasites has sparked significant scientific interest, and multiple laboratories at Cal have begun to explore the CRISPR-based immune system. Jennifer Doudna's lab is trying to sort out the mechanisms of the CRISPR immune system by deducing the structure and function of its constituent proteins. Her lab has recently determined the three dimensional structure of the only protein common to all eight versions of the immune system discovered in different species of bacteria. This protein has the ability to degrade DNA in a test tube, supporting the group's hypothesis that it is involved in early stages of CRISPR-based immunity, such as viral DNA recognition and processing into the CRISPR region. Studying this mechanism sheds light on the tactics employed by bacteria in their ongoing battle with viruses, but understanding the full extent of the war requires studying the entire microscopic ecosystem in action.

Jill Banfield's lab, in the Departments of Earth and Planetary Science and Environmental Science, Policy, and Management, is addressing this question by studying the interdependent population dynamics between bacteria and viruses in the environment. Christine Sun, a graduate student in the Banfield lab, explains their interest in a particular model ecosystem known as "acid mine drainage," the result of erosion from metal or coal mines. "It's a really acid rich environment, where the pH can go down below 1, and so very few organisms can thrive in these areas." Because this niche ecosystem is so inhospitable, the lab can sequence samples of DNA from the environment, determine exactly which microorganisms were present, and even reconstruct complete genomes for many of them. "Over the years Jill has characterized the microbial community," says Sun, "and now we're looking at how viruses and microbes co-evolve."

The Banfield lab is excited about the CRISPR system because it provides a "historical" genetic record of which viruses have infected which bacteria. This information is enabling microbial ecologists to study the interplay between these populations in their native environment, eliminating the need for cultured samples in the laboratory. By sequencing samples taken from the ecosystem at different times, the group's research has uncovered that both the viruses and bacteria have been evolving at an incredibly rapid rate. Once bacteria have targeted a viral sequence in their CRISPR region, the selective pressure to survive drives the viruses to change the sequences of their genome to avoid destruction by the bacterial immune system. Thus, the CRISPR system is actively influencing the diversity of the microbial population and driving the evolution of the ecosystem.

How could the revelation that bacteria use adaptive immune systems to ward off viral pathogens impact higher organisms, like people? "We're studying this CRISPR-virus interaction in acid mine drainage, but it could be applied to any system in which you have microbial communities," says Sun. Bacterial communities involved in commercial processes such as yogurt production and biofuel generation are of particular interest. "That's going to require that they're grown in high density and confined situations," says Wiedenheft. "And what happens in those situations, just like in human populations, is that a virus can really spread and wipe out an entire population. It can shut down your whole operation. If we can immunize bacteria against the viruses that infect those bugs that we're exploiting, then that has obvious economic consequence and benefit." Thus, as we gather new intelligence about the CRISPR immune system, humans stand to become beneficiaries in the ongoing war between bacteria and phage.

Katie Berry is a graduate student in chemistry.

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