Long-term unisexual infection with Schistosoma mansoni in mice has the potential to boost the immune response to oviposition of challenge infection

Abstract text

Background: The complexity of Schistosoma spp. life cycle and their highly effective immune evasion strategies, makes vaccine development challenging. Unisexual infection, excluding immunomodulatory parasite eggs, offers a distinct perspective on host immune responses to both worm sexes and thus may provide a better understanding of complex immunological processes and identification of new targets for vaccine research. We have recently shown that in mice, a long-term unisexual infection with schistosomes leads to an unpolarized Th1/Th2 response associated with an abnormally enlarged spleen and diffuse hepatic inflammation. Aim: In this study, we analyzed whether unisexual worms can mate after 3 months of single sex infection and thus the Th2 response induced by oviposition can reverse or heal the described systemic inflammation. Methods: Mice were infected with male or female cercariae and reinfected with the opposite sex after 12 weeks for the same period. Unisexually infected mice and bisexually infected mice served as controls. At 24 weeks after initial infection, we histologically examined worm mating as evidenced by presence of eggs, infection-related pathology associated with eggs and characterization of liver fibrosis. We analyzed the immune status of the livers and spleens by using flow cytometry, recorded blood cell composition, and performed gene expression analysis of the livers. Results: We found that unisexual worms find each other, mate, and start oviposition even after 3 months. However, we observed more severe hepatic fibrosis in the reinfected groups compared to the bisexually infected group. Egg deposition has been associated with a typical Th2 immune response in the liver after reinfection, along with increased CD4+ T cell immune cells recruitment. Our results show that eggs are able to restore the Th1/Th2 immune imbalance of a previous unisexual infection. However, the organ damage caused by the unisexual worms does not subside, but rather provides the basis of egg-induced inflammation. Conclusion: Schistosomes can survive unpaired for a long time and cause severe organ damage. Given that schistosomes can mate several months after unisexual infection and then worm- and egg-related organ damage can accumulate, infection status without egg proof must be considered. Another critical issue is the tendency to crosshybridization of human schistosomes with livestock specific species, which can further contribute to the spread of the parasite.