Unravelling viral strategies that dodge immune systems

EU-LIFE Science Newsletter 3/2016

Collaboration News from VIB and CEITEC

Throughout evolution, mammalian viruses co-evolved with their hosts and developed effective ways to counter and evade the antiviral responses of the host immune system. An international team - including VIB and CEITEC scientists - unraveled a molecular strategy used by the widespread parapox Orf virus to counter the mammalian immune system.

Orf disease or ‘thistle disease’ is highly contagious and causes painful scabby lesions on the lips and nostrils of animals such as sheep, goats and other livestock. As a zoonotic disease, it can also be transmitted to humans. In fact, Orf is in the top 20 most important viral diseases affecting the rural poor in developing countries — especially in economies that depend heavily on animal farming and agriculture. Although seldom fatal, the disease not only potentially leads to high mortality rates in young animals and children when lesions make it impossible for them to eat; lesions can also impact livestock reproduction and make infected hosts vulnerable to other infections.

Coordinated by prof. Savvas Savvides from VIB-Ghent University and spearheaded by Dr. Jan Felix, an international team of scientists rose to the challenge of shedding light onto how Orf dodges the mammalian immune system. Their approach involved the use of various structural biology methods, including x-ray crystallography and electron microscopy, combined with biochemical and biophysical studies.

Through this integrative structural biology approach, the researchers obtained structural and mechanistic insight on how GIF — a protein secreted by the Orf virus — inactivates IL-2 and GM-CSF, two pleiotropic cytokines of the mammalian immune system. The study revealed that GIF uses its structure in distinct ways to target the two cytokines with high affinity. Remarkably, GIF doesn’t share any structural similarity with the cytokine receptors, yet it is able to mimic their ability to bind to IL-2 and GM-CSF to prevent the normal functions of the two cytokines.

By unveiling how GIF works, the scientists have taken an important step towards understanding the molecular virtuosity that viral proteins develop as they evolve, and how they interact with their hosts’ immune systems. Their findings provide the basis for developing antiviral therapies and for exploiting the potency of viral protein structures, like GIF, to target human proteins in a therapeutic context to counter inflammatory diseases and cancer.

Original article: Felix, J., E. Kandiah, S. De Munck, Y. Bloch, G. C. P. van Zundert, K. Pauwels, A. Dansercoer, K. Novanska, R. J. Read, A. M. J. J. Bonvin, B. Vergauwen, K. Verstraete, I. Gutsche and S. N. Savvides (2016). Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF. Nature Communications 7: 13228.

Image: Transmission electron micrograph of Orf virus. Credit: Dr. Graham Beards at en.wikipedia.org