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Summer 2014

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infectious disease

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cytomegalovirus
  

If you have it, you probably don’t know it. Cytomegalovirus, or CMV, is perhaps one of the biggest pathogens you’ve never heard of—big, both proportionately and epidemiologically. It contains approximately 200 genes, compared to HIV’s paltry 18, and it’s everywhere. Once you have it, you have it for life.

The good news is if you’re healthy, it’s harmless. The T cells of your immune system keep it in check, and you’re none the wiser.

The bad news, however, is if you have a medical condition that dampens your immune system, such as HIV infection or a recent organ transplant, the virus can assert itself with a vengeance. The results, sometimes, are life-threatening.

In the June 5 issue of Cell, researchers in the lab of Steven Gygi, an HMS professor of cell biology, report that they discovered a menu of tactical secrets CMV employs. Using mass spectrometry, a tool commonly used in physics and chemistry, the researchers described the dynamics of a CMV infection in a fibroblast, or connective tissue cell, over a three-day course of infection. As a result, the researchers were able to identify ways CMV evades the immune system and to show how certain viral proteins target and destroy human proteins that defend against infection.

“This is an entirely new way of studying the behavior and tactics of viruses,” says Gygi.

Mass spectrometry is usually used to describe and measure small molecules. Inside the tool, molecules are shattered by an electric charge and then brought through a magnetic field where they are characterized one by one.

Traditionally, this tool has not been applicable to the life sciences because biomolecules, such as proteins, are too large for this technique. Over the past 15 years, however, Gygi has been trying new ways of incorporating mass spec into biology. In one approach, known as electrospray, protein subunits are vaporized and then sprayed into a chamber where they are broken apart by helium. The mass spec then sequences the amino acids of each subunit. The molecules are “reassembled” using an algorithm that matches them to a protein database.

Michael Weekes, a postdoctoral researcher in the Gygi lab and an expert in infectious disease, decided to use mass spec for virology and chose CMV. Although widespread, very little is known about the virus.

Weekes took a sample of fibroblasts newly infected with CMV, harvested the proteins from both the virus and the cell, and sprayed them into the mass spec at different times over three days in order to construct a trajectory of infection. The first three days of infection are particularly important for they mark a covert stage during which the virus hijacks the cell, but hasn’t yet begun to destroy it.

The researchers were able to study approximately 8,000 proteins, identifying not only ways that CMV evades the immune system, but also discovering a number of new therapeutic targets. Most notably, they were able to look closely at proteins that live on the cell surface. These proteins are of great interest: Most drugs target them, yet, because cell surface proteins are few in number, they are harder to study than intracellular proteins are.

Weekes and his colleagues found 29 viral proteins living on the cell surface, 23 of which had not previously been discovered. Many of these CMV surface proteins deter immune cells. Others block cellular proteins that activate immunity. In other words, CMV wards off rescuers while disabling a cell’s ability to defend itself.

“So much of this viral genome is dedicated to simply evading the immune system,” says Weekes.

The next step, according to the researchers, would be to identify antibodies against many of these viral proteins and, ideally, to destroy infected cells before they can replicate and spread the pathogen. 

Image: Jan Hinsch/Science Source

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Issue

Body Language
Summer 2014

Topics

infectious disease

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