UNC-TV Science: March 3, 2014
A Few Amino Acids Could Make All the Difference in the Fight Against Dengue
Dengue fever is a common disease in the tropics. So common, in fact, that as many as 400 million people are infected with dengue every year. Mosquitoes transmit four types of dengue virus, each of which can cause fever, headaches, internal bleeding and sometimes even death.
The trouble with fighting dengue is the fact that there are four genetically distinct forms, and when our immune system forms an antibody to one form, the body is still vulnerable to the other three.
But a team of microbiologists and immunologists from UNC School of Medicine recently discovered a way to change one form of dengue into another, which offers a possible method of tricking our bodies into producing antibodies for both.
When a virus, like one of the dengues, infects a human body, the body’s first response is to send a general attack, but as the infection progresses certain immune cells called helper T cells begin to learn what is causing the infection. A helper T cell would find a cell infected with dengue 1, then report back to B-cells, which make antibodies to specifically fight dengue 1, and killer t-cells, which are trained to kill any cells infected with dengue 1.
This is called the adaptive immune system, and that specific knowledge the helper T cell gathers can be used to mount a quick defense if dengue 1 ever comes back. Many vaccines work under the same principle, that by giving your body a benign form of a virus, the helper T cells will learn to fight off that virus so when it attacks for real, your body is already prepared.
After a dengue 1 infection, the body gains the knowledge and builds up a defense against dengue 1, but not dengues 2, 3 and 4. Our bodies design antibodies to attack a very specific part of an invader, called an epitope, and each form of dengue has its own.
So picture dengue’s four forms as brothers, each with his own defining characteristic. His epitope. Dengue 1 has a mullet, dengue 2 has a flat top, dengue 3 has a ponytail and dengue 4 has a crew cut. An antibody looking for dengue 3 will grab him by his ponytail and toss him out, but that same antibody won’t touch dengue 4 because there’s no ponytail there to grab a hold of.
Aravinda de Silva and Ralph Baric, who led the study at UNC, showed that dengue 3’s ponytail is a tiny hinge that holds two parts of a protein together, and dengue 3 antibodies know to go right for the hinge. But de Silva and Baric then swapped out that hinge for one that belonged to dengue 4, kind of like shaving dengue 3’s ponytail down to a crew cut.
They found that the modified dengue 3 grew in cell cultures and primates, but dengue 3 antibodies had absolutely no effect on the modified strain. In fact, when the modified virus infected primates, the primates developed antibodies to dengue 4, and those antibodies actually fought off the new virus.
Thus, by changing dengue 3’s epitope, de Silva and Baric essentially changed dengue 3 into dengue 4 for the purposes of the immune system. They also identified the only epitope for dengue 3, because after they altered one spot on the initial dengue 3 virus, the antibodies had no effect. If there were other epitopes, the antibodies would have fought back against the modified virus, but not as well.
This type of research is important for the future of dengue vaccines. Vaccines work by introducing invaders and their epitopes to the human body in a benign form so that the body has a chance to pre-build the correct antibodies. By figuring out the epitopes of each type of dengue virus, vaccine makers could potentially make a hybrid with the epitopes for all four forms to be used in a vaccine for all forms of dengue.
Baric and de Silva are currently trying to do the same thing with dengue 1 and dengue 3 to see if the effect of swapping out that hinge is the same. Their work appeared in the journal Proceedings of the National Academy of Sciences.
- Daniel Lane
Daniel Lane covers science, medicine and the environment as a reporter/writer. He is currently pursuing a master's degree in medical and science journalism at UNC - Chapel Hill.