Protective immune responses against Schistosoma mansoni infection by immunization with functionally active gut-derived cysteine peptidases alone and in combination with glyceraldehyde 3-phosphate dehydrogenase

Abstract

BackgroundSchistosomiasis, a severe disease caused by parasites of the genus Schistosoma, is prevalent in 74 countries, affecting more than 250 million people, particularly children. We have previously shown that the Schistosoma mansoni gut-derived cysteine peptidase, cathepsin B1 (SmCB1), administered without adjuvant, elicits protection (>60%) against challenge infection of S. mansoni or S. haematobium in outbred, CD-1 mice. Here we compare the immunogenicity and protective potential of another gut-derived cysteine peptidase, S. mansoni cathepsin L3 (SmCL3), alone, and in combination with SmCB1. We also examined whether protective responses could be boosted by including a third non-peptidase schistosome secreted molecule, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH), with the two peptidases.Methodology/Principal findingsWhile adjuvant-free SmCB1 and SmCL3 induced type 2 polarized responses in CD-1 outbred mice those elicited by SmCL3 were far weaker than those induced by SmCB1. Nevertheless, both cysteine peptidases evoked highly significant (P < 0.005) reduction in challenge worm burden (54–65%) as well as worm egg counts and viability. A combination of SmCL3 and SmCB1 did not induce significantly stronger immune responses or higher protection than that achieved using each peptidase alone. However, when the two peptidases were combined with SG3PDH the levels of protection against challenge S. mansoni infection reached 70–76% and were accompanied by highly significant (P < 0.005) decreases in worm egg counts and viability. Similarly, high levels of protection were achieved in hamsters immunized with the cysteine peptidase/SG3PDH-based vaccine.Conclusions/SignificanceGut-derived cysteine peptidases are highly protective against schistosome challenge infection when administered subcutaneously without adjuvant to outbred CD-1 mice and hamsters, and can also act to enhance the efficacy of other schistosome antigens, such as SG3PDH. This cysteine peptidase-based vaccine should now be advanced to experiments in non-human primates and, if shown promise, progressed to Phase 1 safety trials in humans.

Schistosoma mansoniglyceraldehyde-3-phosphate dehydrogenase enhances formation of the blood-clot lysis protein plasmin

“…Our results confirm an association of SmGAPDH with the tegumental surface of the worm. This further reconciles results that previously characterized SmGAPDH as a protective vaccine target (Argiro et al, 2000b;El Ridi and Tallima, 2013;Tallima et al, 2017;Tang et al, 2019). Before these results, how such an intracellular cytosolic enzyme might be accessed by damaging immune effectors was a conundrum.…”

“…GAPDH is best known as a key enzyme in glycolysis, facilitating the conversion of glyceraldehyde-3-phosphate (GAP) in the presence of nicotinamide adenide dinucleotide (NAD) to 1,3-bisphosphoglycerate (1,3BPG) and generating NADH (Seidler, 2013). S. mansoni GAPDH (SmGAPDH) has been previously expressed in an enzymatically active recombinant form (Argiro et al, 2000a;El Ridi et al, 2001, 2004, has been characterized as a potential vaccine candidate and has been shown to be a target for antibodies in the sera of schistosomiasisresistant individuals (Argiro et al, 2000a,b;Dessein et al, 1988;Goudot-Crozel et al, 1989;Tallima et al, 2017;Tang et al, 2019).…”

Analysis of the interactome of Schistosoma mansoni histone deacetylase 8

“…Moreover, Sm CB1 is a promising vaccine candidate because its administration elicits protection against S . mansoni challenge infection in mice and hamsters [ 30 , 31 ]. A direct link with HDACs has never been reported.…”

An immunoinformatics approach for the design of a multi-epitope subunit vaccine for urogenital schistosomiasis

“…Several studies have reported remarkable cases of resistance to PZQ which include the development of heritable trait that maintained drug resistance to PZQ in more than six generations (Devaney, 2006;Doenhoff, Cioli & Utzinger, 2008;Fallon et al, 1996;Masamba et al, 2016;William et al, 2001). Only 13% of targeted population received praziquantel treatment, with the drug not capable of preventing reinfection, requires repeated treatment and its characterised by reduction in efficiency among population with heavy infection (Tallima et al, 2017). With the endemicity of schistosomiasis still on the increase across many countries, with increased cases of Schistosoma resistance to the most used and reliable drug PZQ.…”