veterinary medicine and biomedical sciences
Tiffany Lee, March 27, 2023
Wiebe expands study of poxviruses, immune function
With new funding from the National Institutes of Health, a Husker virologist will advance his work exploring how poxviruses hijack our cellular circuitry during infection, evading host defenses and tuning the environment for unfettered replication.
Matthew Wiebe, an expert in poxvirus-host interactions, recently received a five-year, $2.2 million grant from NIH’s National Institute of Allergy and Infectious Diseases to study how poxviruses capture genes from the host cell, then deploy them to manipulate and disrupt cell signaling pathways during infection. He is particularly interested in how and why poxviruses have evolved to mirror many of the genes and proteins found in host cells.
“One of the ways viruses appear to tap into our cellular circuitry and manipulate it is by having certain genes and proteins that are very similar to ours – but then altering them,” said Wiebe, professor of veterinary and biomedical sciences. “It’s our hypothesis that by understanding why the viruses have made these copies and what they are using the proteins for, we can better understand ourselves, and potentially key weaknesses in our immune system.”
Along with furthering understanding on cellular biology and immune function, findings from the research could identify strategies for fighting viruses and other diseases.
The poxviruses – best known for the variola virus, which causes smallpox – are fertile ground for studying this mimicry. DNA sequencing has revealed close resemblance between viral genes and human cellular genes; closer, even, than the similarities between members of some human gene families.
With the new funding, Wiebe will conduct proteomics and interactome studies on the vaccinia virus to study these “copies” in more detail, exploring how the virus uses the duplicated structures and which cellular signaling pathways they’re involved in. He’ll partner with the university’s Metabolomics and Proteomics Core Facility for some of this work.
Wiebe’s approach is unique in the virology field for its focus on the signaling pathways of kinases and their close cousin, pseudokinases. Kinases are enzymes that catalyze reactions that turn other cellular molecules on and off. Pseudokinases have the same shape and most of the same amino acid pairs as kinases, but they’re missing a few of the critical components driving enzyme activity, rendering them inactive. Wiebe aims to shed light on the purpose of these inactive enzymes in the virus-host interplay.
“Biology doesn’t keep things around, especially in viruses, that have no function,” he said. “So what in the world are these for?”
His hypothesis is that they have multiple roles. Some may regulate traffic, directing other proteins to particular locations in a cell. Some may attach to enzymes, changing their shape and function. And others are likely negative regulators, serving as a brake pedal that slows the pace of certain cellular processes.
Wiebe has been a leader in exploring this third possibility; specifically, his team has demonstrated how the viral pseudokinase B12 inhibits vaccinia replication. Wiebe’s team will extend this trajectory, studying the sometimes counterintuitive ways in which pseudokinases govern viral activity.
Another area of Wiebe’s research is focused on the role of a protein that sits on the frontline of the virus-host battle. BAF – which stands for barrier to autointegration factor – is a tool that either side can harness to its advantage.
The host cell can deploy BAF to thwart viral replication, which it accomplishes by binding to and compacting the viral DNA, making it unreadable. On the other hand, the vaccinia virus can use its B1 kinase to cripple BAF’s DNA-binding ability, making it incapable of stopping proliferation.
Wiebe will advance his work to understand this tug-of-war over BAF. He’ll also investigate other proteins that, like BAF, are capable of playing for either side. These include histones and a protein complex called HUSH, or human silencing hub, a potentially important player in viral expression.
“BAF is the tip of the iceberg,” Wiebe said. “There are many other pathways that are also at the frontline, dictating whether the advantage is shifted to the virus or the cell. Both are fighting over who manipulates certain pathways.”
Revealing the mechanics of these pathways may be relevant to understanding the development of other diseases, such as cancer, infertility, autoimmunity and neurodegeneration. He hopes his research might open the door to new strategies for tackling these problems.
But getting to that point requires embracing the unknown, Wiebe said. That’s why he studies such a broad range of proteins and genes and is excited about novel findings, even when they defy the conventional picture of viral behavior.
“I’m at a stage in my career where I’m trying to embrace confusion, and move toward it,” he said. “There are pros and cons of different genes, and depending on the context, we may detect either one of them. That doesn’t mean it’s not a step forward – it’s another piece of the puzzle and could lead us in a completely novel direction.”
Wiebe’s current team includes postdoctoral researcher Alexandria Krueger and research technicians Zhigang Wang and Ethan Ramsey.
NIH R01 grants are the agency’s original and oldest grant mechanism. They provide support for health-related research and development based on the mission of the NIH.