Aberrant Receptor-Mediated Endocytosis of Schistosoma mansoni Glycoproteins on Host Lipoproteins

Abstract

BackgroundBilharzia 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 FindingsWe 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.ConclusionsTransfer 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.

Virulence factors of schistosomes

“…Independent evidence for this fate comes in part from short term culture experiments to collect vomitus (and inevitably any true surface secretions) [34] that identified Sm200. In addition, this protein has been reported from the lipid fraction of host serum, providing confirmation of its release [52]. What the function of these proteins might be is a matter of conjecture, but it seems likely that the annexin and tetraspanin play a structural role; that leaves Sm200, Sm29, Sm13 and LMWP as potential virulence factors interacting with the host.…”

Human Plasma Lipid Modulation in Schistosomiasis Mansoni Depends on Apolipoprotein E Polymorphism

“…Another suggestion is that the worms shed antigenic glycosyl-phosphatidylinositol (GPI)-anchored proteins into the circulation, which are sequestered by host lipoprotein particles [44]. Subsequent, antibody attack leads to lipoprotein removal by neutrophil endocytosis, although any plasma cholesterol-lowering effect in vivo has yet to be assessed.…”

Proteomic analysis of Schistosoma mansoni egg secretions

“…However, NPC2 may also facilitate the egress of other glycolipids [50]. Moreover, parasite glycoproteins circulating on host low-density lipoprotein particles have been shown to disrupt lipid homeostasis in host immune cells and induce cellular apoptosis [51] and parasite glycolipids may influence pathogenesis and immunity to infection [52]. NPC2 may participate in this exchange of parasite-derived immunomodulatory molecules.…”