Beyond tethering: new insights into the restriction of orthbunyaviruses by tetherin

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Sensitivity to BST-2 restriction correlates with Orthobunyavirus host range

Text by Mariana Varela

Since its unveiling in 2008, countless studies have shown that Bst2/tetherin is able to restrict the replication of a diverse array of viruses. Tetherin is a so-called interferon-stimulated gene (ISG) that plays multiple roles in the host innate immune response to viruses, the structural organization of the cell, and cancer. The work described here was inspired by a previous observation that species-specific differences among tetherin in primates influence the host range of lentiviruses such as HIV.  During our initial studies on Schmallenberg virus (SBV), an orthobunyavirus of ruminants that emerged in Europe in 2012, we noticed that the replication of this virus was impaired in HeLa cells, a cell line known to express high levels of tetherin. We then tried to grow SBV in cell lines stably expressing either the human or the sheep versions of tetherin and noticed that human tetherin restricted SBV replication (about 10 fold) whereas the sheep tetherin did not. We found that human tetherin restricts SBV by reducing the incorporation of viral envelope glycoprotein into virions leading to the release of less infectious virus. This is different from the more familiar mechanism of restriction by tetherin whereby it tethers viruses to the cell membrane. More importantly, we found that the level of restriction of different orthobunyaviruses by tetherin from different species was directly correlated to their host range in nature.  This was perfectly demonstrated when we found that the sheep version of tetherin restricted a human orthobunyavirus –Oropuche virus– in the same way that human tetherin restricted SBV, i.e. by reducing the incorporation of glycoprotein into the envelope of nascent virions.

This study is the first one to show a correlation between orthobunyaviruses host range and their sensitivity to an antiviral gene. However, tetherin is likely only one of the many factors controlling orthobunyavirus species tropism… much more work will be needed to understand the host and ecological barriers for cross-species transmission of this fascinating group of viruses.


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Differential restriction of orthobunuyaviruses by tetherin. SBV, Akabane virus (AKAV), Sathuperi virus (SATV), Cache Valley virus (CVV), Oropouche virus (OROV) and La Crosse virus (LACV) growth kinetics in (A) human (293-hBST2) and in (B) ovine (293-oBST2A and 293-oBST2B) tetherin-expressing cells.

Introducing the authors


Pictured are Massimo Palmarini and Mariana Varela from the Centre for Virus Research, University of Glasgow, UK.

About the research

Sensitivity to BST-2 restriction correlates with Orthobunyavirus host range
Mariana Varela, Ilaria M. Piras, Catrina Mullan, Xiaohong Shi, Natasha L. Tilston-Lunel, Rute Maria Pinto, Aislynn Taggart, Stephen R. Welch, Stuart J.D. Neil, Felix Kreher, Richard M. Elliott, Massimo Palmarini
Virology, Volume 509, September 2017, Pages 121-130, open access