Specific Antibodies and Arachidonic Acid Mediate the Protection Induced by the Schistosoma mansoni Cysteine Peptidase-Based Vaccine in Mice

Abstract

Several reports have documented the reproducible and considerable efficacy of the cysteine peptidase-based schistosomiasis vaccine in the protection of mice and hamsters against infection with Schistosoma mansoni and Schistosomahaematobium, respectively. Here, we attempt to identify and define the protection mechanism(s) of the vaccine in the outbred CD-1 mice-S. mansoni model. Mice were percutaneously exposed to S. mansoni cercariae following immunization twice with 0 or 10 μg S. mansoni recombinant cathepsin B1 (SmCB1) or L3 (SmCL3). They were examined at specified intervals post infection (pi) for the level of serum antibodies, uric acid, which amplifies type 2 immune responses and is an anti-oxidant, lipids, in particular, arachidonic acid (ARA), which is an endoschistosomicide and ovocide, as well as uric acid and ARA in the lung and liver. Memory IgG1, IgG2a, and IgG2b antibodies to the cysteine peptidase immunogen were detectable at and following day 17 pi. Serum, lung, and liver uric acid levels in immunized mice were higher than in naïve and unimmunized mice, likely as a consequence of cysteine peptidase-mediated catabolic activity. Increased circulating uric acid in cysteine peptidase-immunized mice was associated with elevation in the amount of ARA in lung and liver at every test interval, and in serum starting at day 17 pi. Together, the results suggest the collaboration of humoral antibodies and ARA schistosomicidal potential in the attrition of challenge S. mansoni (p < 0.0005) at the liver stage, and ARA direct parasite egg killing (p < 0.005). The anti-oxidant and reactive oxygen species-scavenger properties of uric acid may be responsible for the cysteine peptidase vaccine protection ceiling. This article represents a step towards clarifying the protection mechanism of the cysteine peptidase-based schistosomiasis vaccine.

Increased hepatic interleukin-1, arachidonic acid, and reactive oxygen species mediate the protective potential of peptides shared by gut cysteine peptidases against Schistosoma mansoni infection in mice

“…However, increase in serum IgG2a antibodies to FhCL1 in MAP-1+MAP-2+alum-immunized mice could be related to alum co-administration [ 12 , 13 , 26 ]. Mice of this group showed the highest reduction in challenge worm burden and small intestine egg granulomas number and diameter ( Table 2 and Figs 2 and 3 ), likely because of activation of inflammatory immune cells by antibody/released gut cathepsin complexes, a mechanism of worm attrition discussed previously [ 1 , 2 , 9 ] ( Fig 8 ).…”

“…Arachidonic acid content was additionally evaluated by immunohistochemistry as described previously [ 8 , 9 , 17 ], except that liver sections were exposed to 3% hydrogen peroxide (Sigma) to block endogenous peroxidase activity, then incubated with 0 or 0.5 μg horseradish peroxidase-linked polyclonal antibody to ARA (MyBioSource, MBS2051576) overnight at 10°C. The reaction was visualized with Dako Liquid DAB + Substrate Chromogen System (Agilent Dako, Santa Clara, CA, USA).…”

A comprehensive and critical overview of schistosomiasis vaccine candidates

“…The powerful oxidant stress-inducing properties of ARA are responsible for its schistosomicidal action, but are counteracted by the anti-oxidant properties of uric acid. It was thus sought to avoid the uric acid-inducing capacity of ARA, via use of an enzyme-inactive peptide construct (Tallima et al 2019 , 2020a ; b ).…”

“…It was recently proposed that specific antibodies and the schistosomicide ARA combine towards parasite worm and egg attrition. (Tallima et al 2019(Tallima et al , 2020a. Curiously, EV derived from adult S. mansoni were found to be internalized by vascular endothelial cells and monocytes and to powerfully up regulate ARA metabolism (Kifle et al 2020b).…”

“…The cysteine peptidase vaccine protection was recently found to be associated with high levels of serum antibodies and an increase in the levels of uric acid and ARA in blood and tissues around 17 days post infection (Tallima et al 2019(Tallima et al , 2020a. Uric acid directed the immune responses towards the type 2 axis, increased the antibody response, and elicited an increase in free ARA, responsible for worm and egg attrition.…”