Pre-existing Schistosoma japonicum infection alters the immune response to Plasmodium berghei infection in C57BL/6 mice

BACKGROUND: Since helminths and malaria parasites are often co-endemic, it is important to clarify the immunoregulatory mechanism that occurs during the process of co-infection. A previous study confirmed that dendritic cells (DCs) are involved in the establishment and regulation of the T-cell-mediated immune response to malaria infection. In the current study, distinct response profiles for splenic DCs and regulatory T cell (Treg) responses were assessed to evaluate the effects of a pre-existing Schistosoma japonicum infection on malaria infection. METHODS: Malaria parasitaemia, survival rate, brain histopathology and clinical experimental cerebral malaria (ECM) were assessed in both Plasmodium berghei ANKA-mono-infected and S. japonicum-P. berghei ANKA-co-infected mice. Cell surface/intracellular staining and flow cytometry were used to analyse the level of splenic DC subpopulations, toll-like receptors (TLRs), DC surface molecules, Tregs (CD4(+)CD25(+)Foxp3(+)), IFN-γ/IL-10-secreting Tregs, and IFN-γ(+)/IL-10(+)-Foxp3(-)CD4(+) T cells. IFN-γ, IL-4, IL-5, IL-10 and IL-13 levels were determined in splenocyte supernatants using enzyme-linked immunosorbent assay (ELISA). RESULTS: The co-infected mice had significantly higher malaria parasitaemia, compared with the mono-infected mice, on days 2, 3, 7 and 8 after P. berghei ANKA infection. Mono-infected mice had a slightly lower survival rate, while clinical ECM symptoms, and brain pathology, were significantly more severe during the period of susceptibility to ECM. On days 5 and 8 post P. berghei ANKA infection, co-infected mice had significantly lower levels of CD11c(+)CD11b(+), CD11c(+)CD45R/B220(+), CD11c(+)TLR4(+), CD11c(+)TLR9(+), CD11c(+)MHCII(+), CD11c(+)CD86(+), IFN-γ-secreting Tregs, and IFN-γ(+)Foxp3(-)CD4(+) T cells in single-cell suspensions of splenocytes when compared with P. berghei ANKA-mono-infected mice. Co-infected mice also had significantly lower levels of IFN-γ and higher levels of IL-4, IL-5, and IL-13 in splenocyte supernatants compared to mono-infected mice. There were no differences in the levels of IL-10-secreting Tregs or IL-10(+)Foxp3(-)CD4(+) T cells between co-infected and mono-infected mice. CONCLUSIONS: A Tregs-associated Th2 response plays an important role in protecting against ECM pathology. Pre-existing S. japonicum infection suppressed TLR ligand-induced DC maturation and had an anti-inflammatory effect during malaria infection not only by virtue of its ability to induce Th2 responses, but also by directly suppressing the ability of DC to produce pro-inflammatory mediators.