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| Co-first authors Erin Doherty (left) and Jason Nomburg (right) Photo Credit: Courtesy of Innovative Genomics Institute |
Viruses and their hosts — whether bacteria, animals, or humans — are locked in a constant evolutionary arms race. Cells evolve defenses against viral infection, viruses evolve ways around those defenses, and the cycle continues.
One important weapon that cells use in the fight against viruses is a set of tiny molecular “alarm signals” made of nucleotides: the same chemical building blocks that make up DNA and RNA. When a virus infects a cell, these nucleotide messengers activate powerful immune defenses. To survive, viruses must find ways to shut these signals down. In a new study published in the journal Cell Host & Microbe, IGI researchers reveal that viruses have evolved a surprisingly large and diverse set of enzymes specifically designed to destroy these immune alarm signals, helping them hide from or disable the host’s antiviral defenses.
These enzymes, called 2H phosphodiesterases (2H PDEs), act like molecular scissors that cut nucleotide messengers to prevent them being recognized by the host.
“Before this study, known PDEs were thought to target only a narrow subset of immune signals,” says co-first author Erin Doherty, a postdoc in the Doudna lab.
Using recent machine-learning advances in protein structure prediction, the team scanned thousands of virus genomes and uncovered over 70 previously unknown viral PDEs that infect animals and bacteria. Many of these PDEs are so evolutionarily distinct that traditional sequence-based search methods could not detect them at all — meaning an entire class of immune evasion tools had been hiding in plain sight.
The team found that PDEs differ dramatically in the types of immune signals they can destroy. Some act broadly, cutting many types of immune-activating molecules, while others are highly selective. This specialization appears to allow a virus to silence the host’s antiviral alarm system while avoiding unwanted disruption of other cellular processes. This evolutionary balancing act enables the virus to replicate without triggering cell death.
Using the facilities at the Stanford Synchrotron Radiation Lightsource at the SLAC National Accelerator Laboratory and the Advanced Light Source at Lawrence Berkeley National Laboratory, the team discovered that small structural differences in the “core” of each PDE determine which immune signals it can recognize.
“This suggests that we can begin to predict a viral enzyme’s immune-evasion strategy based on its structure alone,” says Doherty.
In some cases, viruses appear to use a single PDE enzyme to evade multiple immune systems at once, revealing how a single adaptation can undermine multiple layers of host defense.
Because the molecules targeted by viral PDEs are central to immunity in many organisms, including humans, the team hopes that these insights can guide the development of new antiviral therapeutics and give researchers an improved understanding of how viruses evolve to evade immune detection.
Funding: This research was supported by m-CAFEs (Microbial Community Analysis and Functional Evaluation in Soils), a Science Focus Area led by Lawrence Berkeley National Laboratory and based on work supported by the US Department of Energy (DOE), Office of Science, Office of Biological and Environmental Research under contract number DE-AC02-05CH11231, and the James B. Pendleton Charitable Trust.
Published in journal: Cell Host & Microbe
Title: Divergent viral phosphodiesterases for immune signaling evasion
Authors: Erin E. Doherty, Jason Nomburg, Benjamin A. Adler, Santiago Lopez, Kendall Hsieh, Nathan Price, Nurashau Blount, and Jennifer A. Doudna
Source/Credit: Innovative Genomics Institute | Andy Murdock
Reference Number: vi120225_01
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