Abstract
Schistosomiasis is among the major neglected tropical diseases and effective prevention by boosting the immune system is still not available. T cells are key cellular components governing adaptive immune response to various infections. While common laboratory mice, such as C57BL/6, are highly susceptible to schistosomiasis, the SD rats are extremely resistant. However, whether adaptive immunity is necessary for such natural resistance to schistosomiasis in rats remains to be determined. Therefore, it is necessary to establish genetic model deficient in T cells and adaptive immunity on the resistant SD background, and to characterize liver pathology during schistosomiasis. In this study we compared experimental schistosomiasis in highly susceptible C57BL/6 (B6) mice and in resistant SD rats, using cercariae of Schistosoma japonicum. We observed a marked T cell expansion in the spleen of infected B6 mice, but not resistant SD rats. Interestingly, CD3e−/− B6 mice in which T cells are completely absent, the infectious burden of adult worms was significantly higher than that in WT mice, suggesting an anti-parasitic role for T cells in B6 mice during schistosome infection. In further experiments, we established Lck deficient SD rats by using CRISPR/Cas9 in which T cell development was completely abolished. Strikingly, we found that such Lck deficiency in SD rats severely impaired their natural resistance to schistosome infection, and fostered parasite growth. Together with an additional genetic model deficient in T cells, the CD3e−/− SD rats, we confirmed the absence of T cell resulted in loss of natural resistance to schistosome infection, but also mitigated liver immunopathology. Our further experiments showed that regulatory T cell differentiation in infected SD rats was significantly decreased during schistosomiasis, in contrast to significant increase of regulatory T cells in infected B6 mice. These data suggest that T cell mediated immune tolerance facilitates persistent infection in mice but not in SD rats. The demonstration of an important role for T cells in natural resistance of SD rats to schistosomiasis provides experimental evidences supporting the rationale to boost T cell responses in humans to prevent and treat schistosomiasis.
Highlights
Schistosomiasis is a chronic infectious disease that is pandemic in many tropical and sub-tropical regions
The role of the immune system in driving immunopathology in schistosomiasis has been extensively studied, how adaptive immunity contributes to disease resistance during schistosome infection is still not completely understood
We first used T cell deficient CD3e−/− C57BL/6 mice and experimental Schistosoma japonicum infection and further established novel T cell deficient models in SD rats to assess anti-parasite roles of T cells
Summary
Schistosomiasis is a chronic infectious disease that is pandemic in many tropical and sub-tropical regions. There are numerous studies in rodent models that focus on immunopathological roles of both adaptive and innate immune cells in schistosomiasis [7,8], far less is known about the contribution of specific immune cells to parasite clearance, and especially natural resistance to schistosomiasis in non-classical models remain poorly understood. One of the major reasons for lack of studies into natural resistance mechanisms to schistosomiasis using genetically engineered non-classical laboratory animals such as SD rats was that genetically targeting a specific cell type was not feasible before advent of highly efficient genome editing tools. Schistosomiasis is known as consequence of parasite evasion from host immune system damage, the contribution of adaptive immunity to natural resistance in experimental models remain to be determined [9].
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