Staphylococcus aureus is on the “most wanted list” for the National Institutes of Health, making it a major villain in the microbial world, said Robert B. Gennis, an MCB biochemistry professor.
S. aureus also happens to be on the most wanted list in the lab of Thomas Kehl-Fie, MCB professor of microbiology. That’s why Kehl-Fie and Gennis have teamed up, along with research scientist Lici Schurig-Briccio, to probe this deadly bacterium.
Just this past June, a 22-year-old woman from Danville, Illinois, died of a S. aureus infection, according to the Champaign-Urbana News- Gazette. The woman, who had done gymnastics when she was younger, was injured doing a backflip. When she began hallucinating and experiencing a low-grade fever and numbness in her limbs, she was rushed to Carle Hospital in Champaign, eventually passing away from staphylococcus-related meningitis.
What makes S. aureus particularly dangerous is its ability to adapt to so many places in the body.
“Some pathogens infect only one place in the body,” Kehl-Fie said, “but S. aureus can infect everywhere. That’s why it is so hard to treat. It will infect your brain, it will infect your bones, it will infect your skin.”
Gennis pointed out that S. aureus can even collect on an artificial hip, coating the surface and creating havoc. Sometimes, the infection is so great that surgeons have to remove the hip they just installed.
“S. aureus has learned to adapt to environments where there isn’t much for it,” he added. “It protects itself, and it keeps going. That makes it very dangerous.”
“We have to understand what is going on in the bacteria before we can figure out a way to stop them,” Kehl-Fie said. Specifically, his laboratory has been focusing on how bacteria eat and survive in nutrient poor environments, using Staphylococcus aureus as the model system. “You might think of us humans as a smorgasboard of tasty things for the bacteria to eat, but we’re actually quite nutrient poor,” he said. “From bacteria’s perspective, we’re basically taking away the food before they can eat.”
Kehl-Fie’s laboratory concentrates on manganese and zinc because the human body tries to deprive bacteria of those two nutrients—a defense system known as nutritional immunity.
“We fight bacteria by taking those metals away from them, weakening them so other parts of our immune system can come in and attack them with a one-two punch,” he said.
For many years, researchers focused on the deprivation of iron from bacteria, but Kehl-Fie’s work showed that manganese and zinc are also being withheld. His lab mimicked the starvation of S. aureus in vivo, highlighting the important role of the protein, calprotectin.
“Calprotectin is a metal-binding protein that sucks up manganese and zinc at the sites of infection, starving bacteria for these metals,” according to Kehl-Fie. Starving S. aureus of manganese breaks down its defenses against the immune system’s oxidative bursts, which kill bacteria.
But for every move made by the immune system, S. aureus has a countermove. So Kehl-Fie’s and Gennis’s labs are working together to explore how S. aureus adapts to nutritional immunity. They believe the ArlRS system, a two-component response regulator, is important in enabling S. aureus to resist nutritional immunity, but the labs are trying to figure out how it works.
Bacteria have a sweet tooth, Kehl-Fie noted. But his lab discovered that restricting metals can force S. aureus to eat other carbon sources instead.
“We think that starving S. aureus of manganese actually changes what these bacteria eat,” he said. “They go from having a sweet tooth to preferring steak.”
Gennis said these findings dovetail nicely with their research, which shows that the bacterium’s response is quite different if it’s presented with a sugary meal or a meal of protein.
“It’s got a hierarchy of what it’s attracted to,” he said, “and depending on where it finds itself in the body, it adapts to make the best of it.”
“S. aureus would love to eat sugars if it could,” Kehl-Fie pointed out. “But it’s not a question of what it wants to eat, but what it’s forced to eat if it wants to survive.”
Although the labs are working together, Gennis and Schurig-Briccio come at the problem from a different angle than Kehl-Fie. They take a biochemistry approach because Gennis’s lab has a long history of work on the biochemistry of respiration—how oxygen is used to break down foods to generate energy.
“Our lab is interested in bioenergetics,” Gennis said. “We’ve done a lot of work on the fundamentals, and we decided to focus on S. aureus when Lici (Schurig-Briccio) came here. We’re trying to take what we learned with various enzymes from different organisms and see how it applies to S. aureus.”
During infections, Schurig-Briccio said, bacteria need to extract energy from many different environments in the body. S. aureus has to figure out a different way to adapt to each
organ in the body—each place that it infects. “So we’re looking at how bacteria change their feeding patterns—their metabolism—to adapt to the different environments, which have different carbon sources, nitrogen sources, and may have either high or low oxygen levels,” she said.
“Metabolism matters,” Gennis added.
Using information from the genome, Gennis and Schurig-Briccio have learned what enzymes are being made or can be made by S. aureus, and he said they have identified what “we think are vulnerable loci—places that
are particularly important for S. aureus under certain conditions.”
Specifically, they are looking at certain NADH-dependent enzymes, which are important for oxidation.
“What would happen if you eliminate the capacity of the bacteria to use that enzyme?” Gennis asked. “How would it adapt to that loss? That’s giving us a window into how S. aureus adapts.” And you have to learn how the bacterium adapts before you can find ways to disable it.
The human body is an extreme environment for bacteria, Kehl-Fie pointed out. Humans have entire cells dedicated to killing bacteria, and the body has elaborate systems for starving them, and yet these single-celled organisms can still kill us.
“I’ve always been fascinated by bacteria because they have this phenomenal ability to thrive in distinct and hostile environments,” he said. “How do they do that?”
As Gennis put it, “They’ve got all kinds of nasty tricks.”
