Bilharzia is one of the major parasitic infections affecting the public health and socioeconomic circumstances in (sub) tropical areas. Its causative agents are schistosomes. Since these worms remain in their host for decades, they have developed mechanisms to evade or resist the immune system. Like several other parasites, their surface membranes are coated with a protective layer of glycoproteins that are anchored by a lipid modification.
Methods and Findings
We studied the release of glycosyl-phosphatidylinositol (GPI)-anchored proteins of S. mansoni and found them in the circulation associated with host lipoprotein particles. Host cells endocytosed schistosomal GPI-anchored proteins via their lipoprotein receptor pathway, resulting in disturbed lysosome morphology. In patients suffering from chronic schistosomiasis, antibodies attacked the parasite GPI-anchored glycoproteins that were associated with the patients' own lipoprotein particles. These immunocomplexes were endocytosed by cells carrying an immunoglobulin-Fc receptor, leading to clearance of lipoproteins by the immune system. As a consequence, neutral lipids accumulated in neutrophils of infected hamsters and in human neutrophils incubated with patient serum, and this accumulation was associated with apoptosis and reduced neutrophil viability. Also, Trypanosoma brucei, the parasite that causes sleeping sickness, released its major GPI-anchored glycoprotein VSG221 on lipoprotein particles, demonstrating that this process is generalizable to other pathogens/parasites.
Transfer of parasite antigens to host cells via host lipoproteins disrupts lipid homeostasis in immune cells, promotes neutrophil apoptosis, may result in aberrant antigen presentation in host cells, and thus cause an inefficient immune response against the pathogen.
The finding that GPI-anchored schistosome proteins are transferred from the parasite surface to human lipoproteins may explain how the parasites interfere with an effective immune response.
More than 200 million people live in a close but uneasy alliance with schistosomes, a type of parasitic worm. Like many parasites, schistosomes have a complicated life cycle. They start life by reproducing in fresh-water snails. The snails release free-swimming, infectious parasites, which burrow into the skin of people who swim in the water. The parasites then migrate to the veins draining the gut and mature into 10–20 mm-long adult worms. The worms mate and lay eggs, some of which pass into the feces and so back into water where they hatch and infect fresh snails. Schistosomiasis does not kill many people but it does cause serious health problems. Most of these are caused by the human immune system responding to eggs that get trapped in the veins of the liver, spleen, and gut. Immune cells recognize proteins on the eggs as foreign and organize a hard shell of immune cells and tough fibres around the egg. Eventually, these fibres block the blood vessels in the liver, spleen, and gut, causing locally raised blood pressure, organ damage, and potentially fatal bleeding.
Why Was This Study Done?
Although the immune system mounts a vigorous attack against schistosome eggs, the parasites themselves somehow evade the immune response—adult worms pull off this feat of “invisibility” for years. The researchers who did this study wanted to find out whether the release of glycoproteins (proteins decorated with sugars) from the surface of the schistosome worms is involved in this immune evasion in some way. These glycoproteins (which are anchored to the parasite's surface by a structure called a GPI-anchor; GPI stands for glycosyl-phosphatidylinositol, a sort of fat or lipid) are the major antigens of schistosomes—the molecules that the immune system normally recognizes on foreign intruders.
What Did the Researchers Do and Find?
The researchers first showed that GPI-anchored schistosomal glycoproteins are released into the circulation of patients and there become attached to human lip oproteinparticles (water-soluble carrier molecules that take fats around the body). Then, using cells grown in the laboratory, the researchers discovered that lipoprotein particles loaded with parasite glycoproteins could enter mammalian cells through an interaction with a protein called the low-density lipoprotein receptor, which normally helps cells absorb the lipids needed to make membranes. Once in the cell, the parasite glycoproteins travelled to cellular regions called lysosomes, which they seemed to disrupt. In addition, the researchers found that the parasite glycoproteins could enter mammalian cells by a second route: This involved the glycoproteins being taken up by neutrophils (a type of immune cells). Many of these neutrophils then died, possibly because of the large amount of lipid they accumulated.
What Does This Mean?
These results provide some tantalising clues to how schistosomes might evade the immune response. First, just binding to lipoprotein particles might change how they are seen by the immune system (possible they are not as clearly recognized as foreign substances) and weaken the immune response against them. On the other hand, the damage done to neutrophils by lipid accumulation might also contribute to how schistosomes hide in the human hosts. Neutrophils are an important type of immune cell, and their destruction could compromise the immune system's response to schistosomes. Furthermore, although the researchers do not investigate this possibility, other cells of the immune system that have might also take up these lipids and be damaged. Finally, even if immune cells are not killed outright by lipid accumulation, disruption of their lysosomes might also affect how well the immune system recognizes schistosomes as foreign. The full details of the complex interplay between schistosomes and their hosts remain a mystery, but these results provide intriguing new avenues to explore that might eventually suggest new treatments for schistosomiasis.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030253.
• World Health Organization information on schistosomiasis
• US Centers for Disease Control and Prevention information for the public and for professionals on schistosomiasis
• MedlinePlus encyclopedia entry on schistosomiasis
• Wikipedia page on schistosomiasis (note: Wikipedia is a free online encyclopedia that anyone can edit)