Team learns how sleeping sickness parasite defeats immune system

August 22, 2013 by Bob Yirka report
False-coloured scanning electron microscope images of trypanosomes growing in hepatic vessels of mice after 5 days of infection. Credit: Gilles Vanwalleghem, Daniel Monteyne and David Pérez-Morga, CMMI, Laboratory of Molecular Parasitology, Université Libre de Bruxelles, Belgium

(Medical Xpress)—A team of researchers with members from across Europe has discovered the mechanism by which the sleeping sickness parasite overcomes the immune system in humans. In their paper published in the journal Nature, the team describes the three step process that the parasite uses to defeat an immune system response. They also report that they have developed a mutant type of protein that disrupts the parasitic process allowing the immune system to destroy the invader.

Sleeping sickness is caused by a parasite which is usually transmitted by the fly—7,197 new cases were reported in 2012 alone. It's constrained mainly to Africa and no known vaccine exists to prevent it. In many cases, people who are infected live with it for many years, eventually succumbing to its debilitating effects (headaches, fever, itching, joint pain and eventually swollen lymph nodes and other as well as ). The parasite gains entry to the body when a victim is bitten then travels to other parts of the body via the bloodstream. Modern treatments for the disease have reduced deaths dramatically, but the hope is that a vaccine can be created that will prevent the misery it inflicts.

The researchers have been studying the gambiense strain of the parasite which is responsible for the majority (97 percent) of human deaths. In so doing they have learned that the parasites use a three step process to outwit the .

False-coloured scanning electron microscope images of trypanosomes laying on the peritoneum ephitelium during the first day of infection. Credit: Gilles Vanwalleghem, Daniel Monteyne and David Pérez-Morga, CMMI, Laboratory of Molecular Parasitology, Université Libre de Bruxelles, Belgium

In the first stage, the parasite creates a protein to stiffen its membranes, making it difficult for the apoL1 to enter the parasite body and kill it. The second stage involves building up its inner defenses to make it even more difficult for apol1 to make its way inside. The third stage involves actually digesting the apoL1 protein if it does make its way inside the parasite, preventing its absorption which would kill it.

Because the team was able to identify the process by which the parasite foils the immune system, they were able to develop a mutant strain of the apoL1 protein which was not fooled by the tactics of the parasite and was therefore able to kill it. A lot more research will have to be conducted on the mutant strain of course, to make sure it doesn't behave in unexpected ways, before human trials can begin.

Explore further: Parasite sheds light on sleeping sickness

More information: Mechanism of Trypanosoma brucei gambiense resistance to human serum, Nature (2013) DOI: 10.1038/nature12516

The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1)2, 3, 4. Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR, TLF-2 enters trypanosomes independently of TbHpHbR. APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic ?-sheet of the T. b. gambiense-specific glycoprotein (TgsGP)8, which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa.

Related Stories

Parasite sheds light on sleeping sickness

April 21, 2011
Fresh insight into the survival strategy of the sleeping sickness parasite could help inform treatments for the disease.

Researchers discover how the deadly malaria parasite evades the immune system, make progress toward developing a cure

December 3, 2012
(Medical Xpress)—More than a million people die each year of malaria caused by different strains of the Plasmodium parasite transmitted by the Anopheles mosquito. The medical world has yet to find an effective vaccine against ...

Australian researchers close in on malaria vaccine

July 2, 2013
Australian researchers said Tuesday they were closing in on a potential vaccine against malaria, with a study showing their treatment had protected mice against several strains of the disease.

Variants at gene linked to kidney disease, sleeping sickness resistance

July 31, 2013
(Medical Xpress)—A new study led by University of Pennsylvania researchers involves a classic case of evolution's fickle nature: a genetic mutation that protects against a potentially fatal infectious disease also appears ...

Malaria's severity reset by mosquito

May 30, 2013
(Medical Xpress)—For the first time, researchers have proven that the way in which malaria is transmitted to the host affects how severe the resulting infection will be.

Recommended for you

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

New animal models for hepatitis C could pave the way for a vaccine

July 19, 2017
They say that an ounce of prevention is worth a pound of cure. In the case of hepatitis C—a disease that affects nearly 71 million people worldwide, causing cirrhosis and liver cancer if left untreated—it might be worth ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.