DNA breaks may help parasites elude the immune system
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Parasites have spent millions of years of evolution trying to outsmart the human immune system, and one of their tricks is to change their appearance so that the immune cells no longer recognize them. In the parasite Trypanosoma brucei, which causes African sleeping sickness, new research suggests that a DNA repair pathway accounts for some of their ability to don a disguise.
The key lies in T. brucei’s variant surface glycoproteins, which coat the parasite’s surface. Each parasite only makes one of these glycoproteins at a time, and switching between them helps T. brucei outwit the immune system.
Variant surface glycoproteins can be switched in a number of ways, says George A.M. Cross, the André and Bella Meyer Professor and head of the Laboratory of Molecular Parasitology. “There are about 20 sites within the parasite’s genome that control variant surface glycoprotein expression. Transcription can be shifted from one to another, or a variant surface glycoprotein gene that isn’t being transcribed can be copied to an active expression site in a process called duplicative gene conversion,” says Cross.
To understand how trypanosomes accomplish this conversion, postdoctoral associate Oliver Dreesen made mutant parasites that lacked the telomerase protein. Telomerase is normally essential for the maintenance of telomeres — specialized areas of DNA located at the ends of chromosomes and adjacent to variant surface glycoprotein expression sites. In the absence of telomerase, telomeres would become shorter each time the cells divided, and most of the cells would be expected, eventually, to die. After waiting through more than two years of continuous cultivation, until the telomeres became critically short, it was found that the telomeres at short silent expression sites were unexpectedly stabilized, in the absence of the machinery that is normally responsible for their maintenance. At the active expression sites, however, short telomeres were more vulnerable to breakage, and variant surface glycoprotein genes were gradually lost and then replaced through duplicative gene conversion events that also replaced the telomeres.
“We suspect that, at short telomeres, truncations may fall in regions of the DNA just under the telomeres, which results in strand breakage,” says Cross. “To repair the break, the template can be taken from any neighboring subtelomeric site, resulting in a new variant surface glycoprotein.” That new protein, in turn, alters T. brucei’s external appearance, and serves to disguise the identity of the parasite from the host’s immune system.
