How Congenital Cytomegalovirus Tricks The Immune System

Scientists from Cardiff University think they now know why congenital cytomegalovirus (CMV) is so effective at evading the immune system. The discovery could help treat the virus that is responsible for 1,000 birth defects a year in the UK alone.

The findings show how a large number of CMV genes help it hide from the immune system by destroying many of the proteins produced by the body during virus infection and preventing them from activating immune cells to destroy the virus. Ceri Fielding from Cardiff University School of Medicine, said:

“The scale of the effect of CMV’s genes on the immune system surprised us. The number of immune activating proteins destroyed by these virus genes was unprecedented given any previous discoveries of virus immune evasion strategies. In addition to providing new information that could help develop novel treatments or a cure for this virus, the findings can also tell us more about how our immune system recognizes virus infections beyond CMV.”

Cytomegalovirus Evasion

Congenital CMV is one of eight herpes viruses that can infect humans, one of the leading causes of hearing loss in children and one of the main causes of childhood disability. It is the most complex human virus and causes lifelong infection.

Most healthy adults and children who become infected will have no signs or symptoms and no long-term effects. It can however pose serious risks to unborn babies if a pregnant woman catches it for the first time and is a major problem for people with impaired immune systems.

Natural killer cells are known to play a critical role in detecting and destroying cells infected with CMV. The virus, in turn, has nine genes that help to protect it against natural killer cells.

This includes two genes that belong to a group of similar genes called the US12 family, but it is not clear whether other members of this gene family also provide protection against natural killer cells.

US12 Gene Family

The researchers showed that at least four members of the US12 gene family help CMV to evade natural killer cells. For example, two members work together to target a human protein called B7-H6 that acts a sensor to alert natural killer cells if a particular cell is infected.

However, the impact of the US12 family goes even wider. The whole family works together to control proteins that are found on the surface of human cells, and many of these proteins appear to be involved in regulating the immune response.

The findings provide an insight into how the US12 gene family works, and how CMV has evolved to escape the human immune system. New therapies to control CMV infections are urgently needed so the next challenge is to design new antiviral agents that will target CMV’s defence systems.

The work was funded by the Wellcome Trust, Czech Science Foundation, European Research Council and the National Institute of Health.

Ceri A Fielding Michael P Weekes Luis V Nobre Eva Ruckova Gavin S Wilkie Joao A Paulo Chiwen Chang Nicolás M Suárez James A Davies Robin Antrobus Richard J Stanton Rebecca J Aicheler Hester Nichols Borek Vojtesek John Trowsdale Andrew J Davison Steven P Gygi Peter Tomasec Paul J Lehner Gavin W G Wilkinson
Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation
eLife 2017;6:e22206

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