While smallpox was considered officially eradicated by the World Health Organization in 1980, concerns about its use as a bioterrorism agent – and the finding that other poxviruses, such as monkeypox, can be transmitted from animals to humans – have spurred renewed interest in understanding how they replicate. Having this information in hand could lead to the development of better antiviral strategies.
New research from scientists at Fred Hutchinson Cancer Research Center and collaborating institutions has uncovered how poxviruses evolve to rapidly adapt against host defenses – despite their low mutation rates.
The discovery provides new insight into how large, double-stranded DNA viruses evade host immunity and become drug resistant, and it has particular implications for understanding the mechanisms of infectious-disease transmission between animals and humans.
Senior author Harmit S. Malik, Ph.D., a member of the Hutchinson Center’s Basic Sciences Division, and first author Nels C. Elde, Ph.D., a former postdoctoral researcher in Malik’s lab, describe their findings online ahead of the Aug. 17 print issue of Cell.
“Poxviruses encode a variety of genes that help them to counter host immune defenses and promote infection,” said Elde, now an assistant professor of human genetics at the University of Utah School of Medicine. “Despite ample evidence that the poxvirus genome can undergo adaptive changes to overcome evolving host defenses, we still don’t know that much about the mechanisms involved in that adaptation.”
To determine the mechanisms of adaptation, Elde, Malik and colleagues conducted an experiment in cell culture using vaccinia virus, the type of poxvirus used in the smallpox vaccine, to mimic viral adaptation and evolution as it occurs in nature.
Previous research had demonstrated that a host-defense protein called protein kinase R (PKR) is a major hurdle to poxvirus infection. In response, poxviruses have evolved to overcome PKR by encoding two genes, K3L and E3L, which thwart host-defense mechanisms that normally prevent viral infection.
The team studied how vaccinia virus, when altered to delete the E3L gene, evolved to successfully replicate in the presence of human PKR.
“Dramatically, serial propagation of this ‘weaker’ virus rapidly resulted in strains that became much more successful at replicating in human cells,” said Malik, who is also an Early Career Scientist of the Howard Hughes Medical Institute.
Closer examination of their mode of adaptation revealed that the virus was quickly able to defeat PKR by selectively increasing the number of copies of the K3L gene in its genome.
Malik likened this rapid adaptation to the expansion of the bellows of a musical accordion. “As the K3L copy number increased in subsequent rounds of replication, so did expression of the K3L protein and subsequent inhibition of the immune response,” he said. This showed that viruses that can quickly expand their genome have an immediate evolutionary advantage over those that cannot.
In a further extension of the accordion analogy, in addition to observing rapid gene expansion in the E3L-deficient strain of vaccinia, the researchers also observed that the virus contracted after acquiring an adaptive mutation, swapping a beneficial mutation for a smaller genomic footprint.
“Our studies suggest that despite their transient nature, gene expansions may provide a potent means of adaptation in poxviruses, allowing them to survive either immune or pharmacological challenges,” Malik said. “Recognizing the means by which they undergo this expansion may provide more effective antiviral strategies against these and related important pathogens.”
The National Institutes of Health, the National Science Foundation, the Howard Hughes Medical Institute and the Life Sciences Research Foundation funded the research. In addition to researchers at the Hutchinson Center and University of Utah School of Medicine, the study also involved collaborators at the University of Washington School of Medicine.
Note for media only: To obtain a copy of the Cell paper, “Poxviruses deploy genomic accordions to adapt rapidly against host antiviral defenses,” please visit firstname.lastname@example.org.
At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit www.fhcrc.org.
Kristen Woodward | Newswise Science News
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
29.03.2017 | Materials Sciences
29.03.2017 | Physics and Astronomy
29.03.2017 | Earth Sciences