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���������� Boulder researcher Aaron Whiteley is recognized by the American Society for Microbiology for his work exploring bacterial immune responses and how it translates to the human immune system

A University of Colorado Boulder researcher has been recognized with the 2024 American Society for Microbiology for his work exploring how bacterial immune systems recognize and respond to phage infection.

Aaron Whiteley, an assistant professor of biochemistry, was honored for his research finding that bacterial and human immune systems are highly related and share a common ancestor. He and his research colleagues in the Whiteley Lab study what bacterial immune response can indicate about host-pathogen interactions and the mechanisms of signaling in human cells.

By focusing on specific signaling pathways in bacteria and human cells, particularly the cGAS-STING pathway, Whiteley hopes to better understand the role they play in resistance to infectious disease and cancer. Better understanding can inform better, more-targeted therapeutics.

Common ancestors

Whiteley’s research began with an interest in host-pathogen interactions, “how viruses and bacteria make humans sick,” he says. “And more generally, I’ve always been interested in aspects of microbiology, how bacterial organisms go about their daily life.

���������� Boulder researcher Aaron Whiteley recently was recognized by the American Society for Microbiology with the 2024 Award for Early Career Basic Research.

During his post-doctoral studies, he worked on research studying how bacteria defend themselves against phages, which are viruses that infect and replicate only in bacterial cells and are the in the biosphere. He was electrified by the discovery of an enzyme that not only defends against phages, but whose homologue—or a gene inherited in two species from a common ancestry—defended human cells against viruses.

That led him to the study of phages and common ancestors that both human cells and bacteria share.

“We tend to think of the human immune system as this intricate system of genes that maybe animals invented in isolation,” Whiteley says. “What our and other research has shown is that probably over a billion years ago, bacteria and unicellular animals were interacting. Maybe the animal was eating the bacteria, because somehow the genes in the bacteria got into the germ line of that animal.

“If the gene was anti-viral in bacteria, it was anti-viral in the animal cell, which is probably why we kept it. It was stolen from bacteria and now used to detect viruses that would make animals sick. Mice have these genes, we have these genes, bacteria have these genes. Our contention is that if we can figure out how this immune response works in bacteria, we can better understand how it works in human cells.”

Studying immune signaling

Whiteley and his research group focus on two major families of immune signaling or innate immune genes: cGAS, which plays a critical role in immunity by detecting foreign DNA, and NLR-related proteins.

“NLRs in human cells detect all sorts of pathogens, and we’ve found them in bacteria, which has been really cool,” Whiteley says. “We’ve been trying to understand how they work; the main emphasis is how they sense the virus. How does the cell see to know that there’s a virus inside of it?

“That’s a really tough question biochemically for a bacterium to figure out. Viruses are so good at stripping themselves down to just their genome, so this is a fascinating problem that viruses and hosts have been arguing over: Viruses are trying to become the most minimal and most inconspicuous, and the host is looking for any molecular signal to recognize them.”

Every time researchers think a host has outsmarted the virus, Whiteley says, they discover that the virus has made another protein that inhibits the host’s detection system. “Viruses always seem to have the upper hand, yet we’re still here,” Whiteley says. “In both our immune system and the bacterial immune system, there isn’t just one pathway; there are hundreds.”

Whiteley notes that while the human immune system is essentially the same between individuals, there may be few or no similarities in immune systems between two bacteria plucked from the wild. For example, two E. coli cells may have dozens of different pathways for detecting the virus and no similarities between the two cells.

“So, the virus now has to keep up with all of those different pathways in each individual cell,” Whiteley says. “E. coli have figured out how to decentralize this knowledge and spread it out all over, which probably contributes to why any host still exists.”

Better at treating disease

By understanding the ancestors of these signaling proteins present in human cells and originating in bacterial ones, Whiteley and his lab group aim to understand fundamental qualities of the human immune system.

“We haven’t actually diversified that much from our bacterial roots,” he says. “The protein structures are the same, so if we can understand what these proteins do in bacteria then it may be much easier to apply that understanding to humans. If we can figure out how bacteria turn them on, that might be a good understanding that can inform the next RNA vaccine.”

A mutated version of human NLRs is associated with ulcerative colitis and inflammatory bowel disease, so understanding how the NLRs are signaling generally may lead to better treatments. There also is a potential to develop better caner immunotherapy drugs and treatments for autoimmune disease through understanding the cGAS-STING pathway.

“Anti-phage proteins seem to have great applications in biotech and I’m excited to continue working on that,” Whiteley says. “We’ve developed a biosensor for the human cGAS pathway and maybe down the road that will help us understand whether a cancer patient is going to respond to a particular treatment.

“If we can better understand how to turn more of a person’s immune system on or make sure they’re taking the right drug ahead of that activation, I think we’re going to be much better at treating disease.”

Top image: phages on a bacteria cell (source: Eye of Science/Science Source)

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