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

Hein Sprong,Alexandra Van Remoortere,Monika Suchanek,Judith Klumperman,Jeanette H W Leusen,Jaap J Van Hellemond,Christoph Thiele,Diana Avram,Suzanne M Van Dijk,Joke Van Der Linden

doi:10.1371/journal.pmed.0030253

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.

Highlights

Schistosomiasis, known as bilharzia, is a chronic disease caused by parasitic Schistosoma flatworm species [1] that affects more than 200 million people worldwide
We studied the release of glycosyl-phosphatidylinositol (GPI)-anchored proteins of S. mansoni and found them in the circulation associated with host lipoprotein particles
Adult schistosomes release proteins and lipids from their surface into the circulation [34]. To investigate whether they are present on lipoprotein particles, sera from patients chronically infected with S. mansoni were cleared of parasite remnants and membrane fragments by high-speed centrifugation and analysed by isopycnic density centrifugation (Figure 1A)

Summary

Introduction

Schistosomiasis, known as bilharzia, is a chronic disease caused by parasitic Schistosoma flatworm species [1] that affects more than 200 million people worldwide. GPI-anchored proteins are abundant in parasites and have an important role in cell viability and defence against the host immune system [5,6] They can be shed into the medium by the action of proteases or phospholipases [7] or released on membranous particles [8À11]. Trypanosome surface GPI protein has been observed on host erythrocytes [18], and retrograde transfer of host GPI protein onto the parasite was found in schistosomes [19] It is not known how this transfer works mechanistically nor whether lipoprotein particles are involved. 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. These fibres block the blood vessels in the liver, spleen, and gut, causing locally raised blood pressure, organ damage, and potentially fatal bleeding

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