Schistosoma haematobium Extracellular Vesicle Proteins Confer Protection in a Heterologous Model of Schistosomiasis

Abstract

Helminth parasites release extracellular vesicles which interact with the surrounding host tissues, mediating host–parasite communication and other fundamental processes of parasitism. As such, vesicle proteins present attractive targets for the development of novel intervention strategies to control these parasites and the diseases they cause. Herein, we describe the first proteomic analysis by LC-MS/MS of two types of extracellular vesicles (exosome-like, 120 k pellet vesicles and microvesicle-like, 15 k pellet vesicles) from adult Schistosoma haematobium worms. A total of 57 and 330 proteins were identified in the 120 k pellet vesicles and larger 15 k pellet vesicles, respectively, and some of the most abundant molecules included homologues of known helminth vaccine and diagnostic candidates such as Sm-TSP2, Sm23, glutathione S-transferase, saponins and aminopeptidases. Tetraspanins were highly represented in the analysis and found in both vesicle types. Vaccination of mice with recombinant versions of three of these tetraspanins induced protection in a heterologous challenge (S. mansoni) model of infection, resulting in significant reductions (averaged across two independent trials) in liver (47%, 38% and 41%) and intestinal (47%, 45% and 41%) egg burdens. These findings offer insight into the mechanisms by which anti-tetraspanin antibodies confer protection and highlight the potential that extracellular vesicle surface proteins offer as anti-helminth vaccines.

A comprehensive and critical overview of schistosomiasis vaccine candidates

“…Recently, TSPs were found to be localized in adults S. mansoni and S. hematobium tegument vesicles, not on the surface membrane (Schulte et al 2013 ; Sotillo et al 2015 ), supporting a mechanism of action via release in EVs (i.e. ESP) (Sotillo et al 2016 ; Samoil et al 2018 ; Kifle et al 2020a ; Mekonnen et al 2020 ). The study of Mekonnen et al ( 2020 ) reported that ShTSP-2 conferred a highly significant protection against heterologous challenge ( S. mansoni ) model of infection.…”

“…ESP) (Sotillo et al 2016 ; Samoil et al 2018 ; Kifle et al 2020a ; Mekonnen et al 2020 ). The study of Mekonnen et al ( 2020 ) reported that ShTSP-2 conferred a highly significant protection against heterologous challenge ( S. mansoni ) model of infection. However, it is not clear how the ability of anti-TSP antibodies to block vesicle uptake by host target cells explains the potential of TSPs as promising anti-fluke vaccine (Kifle et al 2020b ).…”

“…It was recently documented that actually all S. mansoni and S. haematobium surface membrane, tegumental and digestive tract candidate vaccine antigens are ESPs, readily detectable in worm derived 15 k (286 proteins) and 120 k (716 proteins) EVs. Sm23, SG3PDH, calpain, Sm-TSP-2, saponin B domain-containing proteins, GST, Sm29, cathepsin domain-containing proteins namely cathepsin B and cathepsin L, proteases, oxidants were identified (Sotillo et al 2016 ; Samoil et al 2018 ; Kifle et al 2020a ; Mekonnen et al 2020 ). El Ridi and Tallima ( 2009 , 2013a ) and El Ridi et al ( 2015 ) were the first to advocate that vaccine candidates should only be sought among the developing and migrating larvae ESPs because ESPs are able to induce innate and adaptive immunity and are accessible targets to host immune elements.…”

Trematode Proteomics: Recent Advances and Future Directions

“…Mass spectrometry profiling was used to show that over half of the proteins previously identified in the secretome of E. caproni and F. hepatica were associated with extracellular vesicles (EVs) that could be enriched by ultracentrifugation of the culture medium of parasites maintained in vitro [ 34 ]. The EV fraction of F. hepatica , S. mansoni, and S. haematobium adult secretions has been further separated into two populations with distinct protein compositions that pellet at either 15,000× g or 120,000× g by ultracentrifugation (named 15K or 120K EVs) [ 35 , 36 , 37 ]. Characterisation of the surface proteins of F. hepatica EVs was enabled by incubating the vesicles with a membrane-impermeable biotin reagent then performing liquid chromatography-tandem mass spectrometry (LC-MS/MS) on proteins isolated by streptavidin pulldown [ 38 ].…”

Extracellular Vesicles: Schistosomal Long-Range Precise Weapon to Manipulate the Immune Response

“…Indeed, epidemiological evidence supports the fact that schistosomiasis can protect against allergy in an endemic population ( Medeiros et al., 2003 ; Oliveira et al., 2014 ). Therefore, exploring the schistosomal ‘strategy’ may facilitate the development of novel diagnostic tools ( Meningher et al., 2017 ; Weerakoon et al., 2018 ; Silva-Moraes et al., 2019 ), vaccines ( Sotillo et al., 2016 ; Mekonnen et al., 2020 ) and therapeutic approaches for human schistosomiasis and immune dysregulation ( Siles-Lucas et al., 2015 ; Ayelign et al., 2020 ).…”