Specific anti-glycan antibodies are sustained during and after parasite clearance in Schistosoma japonicum-infected rhesus macaques

Abstract

BackgroundHuman immunity to Schistosoma infection requires many years of exposure, and multiple infections and treatments to develop. Unlike humans, rhesus macaques clear an established schistosome infection naturally at the same time acquiring immunity towards re-infection. In macaques, schistosome egg production decreases after 8 weeks post-infection and by week 22, physiological impairment of the worm caused by unclarified antibody-mediated processes is observed. Since strong antibody responses have been observed against schistosome glycan antigens in human and animal infections, we here investigate if anti-glycan antibodies are associated with immunity against schistosome infections in macaques.MethodsWe used a microarray containing a large repertoire of glycoprotein- and glycolipid-derived glycans from different schistosome life stages to analyse anti-glycan serum IgG and IgM from S. japonicum-infected macaques during the course of infection and self-cure. We also used an in vitro schistosomula assay to investigate whether macaque sera containing anti-glycan antibodies can kill schistosomula.Conclusions/significanceAntibody responses towards schistosome glycans at week 4 post-infection were dominated by IgM while IgG was high at week 8. The profound increase in IgG was observed mainly for antibodies towards a large subset of glycans that contain (multi-)fucosylated terminal GalNAcβ1-4GlcNAc (LDN), and Galβ1-4(Fucα1–3)GlcNAc (LeX) motifs. In general, glycans with a higher degree of fucosylation gave rise to stronger antibody responses than non-fucosylated glycans. Interestingly, even though many IgG and IgM responses had declined by week 22 post-infection, IgG towards O-glycans with highly fucosylated LDN motifs remained. When incubating macaque serum with schistosomula in vitro, schistosomula death was positively correlated with the duration of infection of macaques; macaque serum taken 22 weeks post-infection caused most schistosomula to die, suggesting the presence of potentially protective antibodies. We hypothesize that IgGs against highly fucosylated LDN motifs that remain when the worms deteriorate are associated with infection clearance and the resistance to re-infection in macaques.

Glycan Microarray-Assisted Identification of IgG Subclass Targets in Schistosomiasis

“…In contrast, IgG2 response in this pool was mainly directed toward core xylose containing N-glycans. Core α3-fucose has been shown to be an antigenic target in schistosome-infected humans, mice and rhesus macaques ( 12 , 15 ). Interestingly, alone or in combination with core xylose, core α3-fucose also forms the major cross-reactive carbohydrate epitopes that are IgE targets on a variety of plant-derived allergens ( 28 , 32 , 33 ).…”

“…Previously we have studied the anti-glycan IgG and IgM responses in schistosome infected rhesus macaques that are able to expel the worms ( 15 ), in order to identify glycan targets of antibodies that might be involved in the self-cure mechanism. We showed that serum IgG antibodies against highly fucosylated schistosome glycoproteins and glycolipids formed during infection were sustained when the macaques cleared the infection, indicating that these antibodies are present in a protective context and possibly play a role in the killing of adult worms in the host.…”

“…We showed that serum IgG antibodies against highly fucosylated schistosome glycoproteins and glycolipids formed during infection were sustained when the macaques cleared the infection, indicating that these antibodies are present in a protective context and possibly play a role in the killing of adult worms in the host. Additionally, sera from macaques containing high titres of IgG against highly fucosylated motifs were able to kill schistosomula in vitro ( 15 ) and it has been shown that a monoclonal antibody specific for the fucosylated LeX antigen was protective in a mouse model of S. mansoni infection ( 6 ). On the other hand, humans that are generally susceptible to reinfection also have high titres of IgG antibodies against highly fucosylated motifs ( 16 ), indicating that anti-glycan antibodies are not necessarily protective.…”

Antibody responses to Schistosoma mansoni schistosomula antigens

“…For instance, anti‐glycan IgG protects mice against challenge with S. japonicum . Furthermore, glycan‐specific IgG antibodies have been associated with the ability of nonhuman primates to naturally clear Schistosoma infections . In the present study, the recombinant schistosomula proteins were generated in an E. coli system without the ability to glycosylate proteins.…”

TLR Specific Immune Responses against Helminth Infections

“…Similar findings have been reported in the immune response to Ascaris lumbricoides . Glycans may also play a role in resistance to Schistosoma japonicum [ 104 ]. In addition to TLR2, TLR9 may promote host protective immune responses.…”