I have just returned from a Keystone Symposia conference in New Orleans on malaria which brought together some of the world's leading experts in combating and treating this devastating disease. The participating scientists and clinicians reported that approximately one million people, primarily children, die from malaria every year and many, many more suffer severe illness. Efforts to control malaria range from eliminating the mosquitos that spread the disease through spraying and insecticide-treated bed nets, to anti-malarial drugs and vaccines. Progress is being made, but the pace is slow and the prospects for a malaria-free world are still a distant hope. However, the mood at the conference was quite optimistic.
Malaria gets its name from the medieval Italian mala aria (which means bad air) and is derived from the false assumption that malaria was spread through the air. We now know that the malaria parasites are spread through mosquito bites, effectively being injected directly into the bloodstream. Once in the blood, the parasite travels to the liver where it produces many copies of itself and then re-enters the blood and finds a new home in red blood cells. The large number of parasites in the blood and liver causes severe fever and, in some cases, complications that can result in death. The cycle is repeated when a mosquito seeks a new blood meal and bites an infected person, thereby picking up the parasite for spread to a new individual.
A particularly intriguing topic of discussion at the conference concerned the immune system's response to infection. Contraction of malaria can result in severe fever caused by the immune system's attack on the parasite. The parasite is clever, though, and has evolved multiple strategies to evade most of the body's immune attack and persist long enough to allow transfer to a new mosquito. A key player in the early immune response is a molecule called a "toll-like" receptor. Toll-like receptors are part of a family of molecules that act as sensors, or smoke alarms, that something is wrong. They specifically detect abnormal components in the body, such as bacterial cell walls, the unusual sugars present in fungi or the distinct genetic material found in some viruses. Once a toll sensor is triggered, the immune system spurs into action and makes an appropriate response based on what type of foreign material it detects. When the receptors' function is impaired (through genetic mutation), individuals are severely compromised in their ability to fight infection. In the case of malaria, a molecule called toll-like receptor 9 is triggered by a parasite byproduct, and several other toll-like receptors appear to sense malarial components. Unfortunately, the parasite has learned how to evade immune responses by hiding in red blood cells, providing time for the parasite to flourish (and spread to a new mosquito) before it is eventually controlled by the immune system.
Interestingly, toll-like receptors were initially discovered not in humans, but in flies. The family of molecules was found to be part of the fly's immune system response to infection. When scientists genetically inactivated the gene for one of these receptors, the flies died quickly from devastating fungal infections. It was quickly realized that mammals, including humans, have a virtually identical system of molecules and that these molecules play a fundamental role in the mammalian immune system as a primary sensor mechanism. This discovery led to a Nobel Prize in Physiology or Medicine in 2011.
The similar structures of toll-like receptors in humans and flies indicate that they evolved from a common ancestor during the evolutionary process. They are therefore part of an ancient defense mechanism that protected very primitive animals from the infectious agents of their time. In the case of malaria, this turns out to be important because the toll receptors in mosquitos have been shown to play a key role in controlling malaria parasites in mosquitos. Thus, toll-like receptors play a dual role in the control of malaria by sensing the parasite in both the mosquito and the human host. Paradoxically, while the ability of toll receptors to prevent the parasite from killing the mosquito is wonderful from the mosquito's perspective, it actually facilitates the transmission of the disease since the mosquito can continue to bite humans. However, the realization that these molecules are key in the transmission and pathogenesis of malaria provides exciting targets for vaccines, drugs and insecticides. Advances in the field may also have important benefits for the control of other mosquito-borne diseases such as West Nile Virus closer to home.
David L. "Woody" Woodland, Ph.D. is the Chief Scientific Officer of Silverthorne-based Keystone Symposia on Molecular and Cellular Biology, a nonprofit dedicated to accelerating life science discovery by convening internationally renowned research conferences in Summit County and worldwide. Woody can be reached at (970) 262-1230 ext. 131 or firstname.lastname@example.org.