LONDON ¿ Red blood cells infected with the malarial parasite Plasmodium falciparum can stick to the host¿s cells, such as those lining the blood vessels. In severe malaria, this feature of the disease can cause death because the blood vessels of the brain or, in a pregnant woman, those of the placenta, can become clogged with parasitized cells.
There is more to this sticky quality of the infected cells than simply giving them a safe place to shelter from the hurly burly of the bloodstream. New research has shown that the parasitized cells are damping down the immune response. Specifically, they interfere with the ability of cells of the immune system known as dendritic cells to respond to the infection.
The finding explains why people have a poor immune response to other infections when they are suffering from malaria, as well as why vaccinations are less effective if given to children during an attack of malaria. It could lead to new approaches to vaccines that protect against malaria. A better understanding of exactly how the immune system is disabled by the malaria parasite also could help researchers develop novel therapies to control autoimmune diseases and graft rejection.
David Roberts, a hematologist and research scientist at the Institute of Molecular Medicine at the University of Oxford in the U.K., and at the National Blood Service, also in Oxford, told BioWorld International, ¿This is a really interesting piece of immunological research that I am sure will be the basis for further studies and, I hope, therapeutic advances in the future although it is difficult to say quite what direction these will take.¿
Roberts and his team, funded by the Wellcome Trust (the world¿s largest medical research charity), the German Research Council and the University of Oxford, have applied for a patent for modulating the function of dendritic cells. They are interested in hearing from partners that could help develop their findings.
Their study is reported in the July 1, 1999, Nature in a paper titled, ¿Plasmodium alciparum infected erythrocytes modulate the maturation of dendritic cells.¿
An estimated 500 million people a year become infected with malarial parasites, mostly in sub-Saharan Africa and Asia. An estimated 1 million children die from the disease each year, usually following infection with Plasmodium falciparum. The disease is transmitted by female mosquitoes, which pass on the parasite during a blood meal.
Roberts said he and his team decided some years ago to investigate the disruption of the immune system that occurs during an attack of malaria. Britta Urban, an immunologist at the Institute of Molecular Medicine, decided to look at the interaction between infected cells and dendritic cells. The latter play a key role in the immune response, as they can activate both memory and naive T cells.
Urban told BioWorld International, ¿We found to our surprise that dendritic cells were profoundly affected by malaria-infected red blood cells, and that the way in which the infected cells were able to disarm dendritic cells was by sticking to their surfaces.¿
Normally, when dendritic cells in culture are exposed to an inflammatory stimulus, they upregulate their production of antigen-presenting molecules, such as HLA Class II, and co-stimulatory molecules, such as CD83 and CD86. However, when the group incubated dendritic cells with malaria infected red blood cells before giving the inflammatory stimulus, they found that this upregulation of key molecules did not occur.
Roberts, Urban and colleagues found this only happened when they used a variety of malaria-infected cell that is capable of sticking to host cells. ¿Sticky malaria-infected cells inhibit activation of dendritic cells,¿ Urban said, ¿but non-sticky ones do not.¿
In a series of experiments, the group showed that the inactivated dendritic cells that had been incubated with sticky malaria-infected cells could not activate T cells. These dendritic cells could not stimulate lymphocytes from other people (the mixed lymphocyte reaction), nor could they stimulate a primary or secondary T cell response, nor proliferation of a T cell clone.
The parasite-derived proteins expressed on the surface of malaria-infected cells are known as variant proteins. There are more than 50 of them, all serving the same function of allowing the cell to adhere to host cells. Roberts said, ¿Up till now, people have thought that the main function of these proteins is to let them stick to blood vessels and keep out of the way of the spleen. What we have now shown is that these proteins also help make the parasites stick to dendritic cells of the host and disarm them. It is not the only way in which the parasites evade the immune system but it is a new one.¿
One future study suggested by this finding, Roberts said, is to find out whether more effective vaccination of children in areas where malaria is endemic can be achieved if children suffering from malaria are first treated before being vaccinated. ¿It is possible that the malaria parasites in the blood stream may inhibit an effective immune response, and that can be tested,¿ he said.
Secondly, the team suggests its finding may help in the design of subunits for a vaccine against malaria. Urban said, ¿If these variant proteins are going to be included in a vaccine, then it may be necessary to modify them in some way so that they still retain their antigenicity, but are not able to disable the immune system. This is somewhat speculative, but given the difficulties we are having in designing a malaria vaccine, it is probably worth trying.¿
Most excitingly, Roberts said, ¿the work suggests that the malaria parasite is exploiting a very specific and powerful way of switching off or downregulating the immune system. If we could find out the mechanism, we might be able to exploit it therapeutically and switch off harmful immune responses to foreign proteins or autoimmune disease, such as autoimmune destruction of red blood cells and platelets.¿
It is impossible to be more specific, he said, until more is known about the mechanism by which the parasite does this.