By Phoebe Ingraham Renda
Laura Mike, assistant professor of medicine and PhD candidate Saroj Khadka at their University of Pittsburgh research lab. Photography by Rayni Shiring, University of Pittsburgh.
Imagine entering an unfamiliar room blindfolded. Every object you touch or bump into helps you figure out where you are and what to do next. Bacteria explore their environment in a similar way, but their “internal logic” remains a mystery.
“We think about the bacterial cell surface a lot because it’s the interface between the bacteria and the environment,” says Laura Mike, assistant professor of medicine (Division of Infectious Diseases), School of Medicine, University of Pittsburgh.
Her research focuses on how bacteria sense their environment and modify their cell surface in response. A key example is Klebsiella pneumoniae, a bacterial pathogen ranked among the deadliest worldwide. It has a particularly dangerous pathotype called hypervirulent K. pneumoniae (hvKp), characterized by its ability to become slimy—a trait called hypermucoviscosity (mucoidy). She and Saroj Khadka, a School of Medicine doctoral candidate in microbiology and immunology, have been working to uncover the biological rationale and mechanisms of this trait.
The work arose from an inadvertent discovery Khadka made during a push to finalize a research study.
“We were trying to do some other experiment, and then we were like, ‘this control is just not working,’” recalls Khadka. Scientists, including the members of his dissertation committee, expected the bacteria to grow in a slimy manner when in the presence of sugar. These were not. “But we did not care that much at first, because we just had to finish that paper.”
After finishing the paper, Khadka and Mike revisited the finding and tested a series of sugars that would normally be found in the human gut, where hvKp is often found.
To his surprise, Khadka found that bacteria only needed to take in sugar, not metabolize it, to sharply reduce their sliminess. The discovery showed that the bacteria, previously thought to always be mucoid, were not always in that state. This suggested that the bacteria are actively sensing their environment and adjusting their mucoidy level in response.
Since pathogens like hvKp exploit host nutrients to fuel their growth, colonization and virulence, Mike and Khadka set out to understand how tissue-specific nutrients influence sliminess. For example, amino acids are especially abundant in tissues like the urinary tract and lungs, and their availability plays a key role in whether bacteria can survive and cause disease in those systems.
In a series of two studies published a year apart in Nature Communications, Mike’s lab has been defining what’s regulating hvKp’s responses to different biological contexts and the underlying rationale. In the first publication, led by then-graduate student Brooke Ryan, it was found that in the context of lung infections, hvKp mucoidy is affected by the availability of a common amino acid, arginine. Arginine cued the bacterial cells to become slimy—making them more difficult for immune cells to catch. Yet high levels of sugar, which are often abundant in the context of the gut, had the opposite effect on mucoidy, as shown in the second publication.
Their findings support that environmental nutrients act as regulatory cues for mucoidy, driving the dynamics that contribute to how well hvKp can colonize its environment and cause illness. Understanding these biological mechanisms could lead to new therapeutic strategies, says Mike. By strategically increasing or decreasing nutrient bioavailability, doctors might be able to shift an active infection into a state that’s easier to treat through interventions as simple as dietary changes.
But Mike cautions that there is more complexity to untangle. In real environments, such as the gut, these nutrients rarely exist in isolation; they interact together, which dramatically complicates matters.
“Making sense of how the bacteria process complex environmental signals—like which nutrient has the more dominant effect over another or what happens when there’s no oxygen—is something we would like to understand long term,” says Mike. “Building tools at the bench gives us ways to ask those questions.”