Toxoplasma gondii GRA15(II) effector-induced M1 cells ameliorate liver fibrosis in mice infected with Schistosomiasis japonica.

Recent studies indicated that type II Toxoplasma gondii (Tg) GRA15(II) favored the generation of classically activated macrophages (M1), whereas type I/III TgROP16(I/III) promoted the polarization of alternatively activated macrophages (M2). A number of studies have demonstrated that M2 cells are involved in the pathogenesis of the liver fibrogenesis caused by Schistosoma japonicum. The purpose of the present study was to explore the inhibitory effect of Toxoplasma-derived TgGRA15(II) on mouse hepatic fibrosis with schistosomiasis. The gra15(II) and rop16(I/III) genes were amplified from strains T. gondii PRU and Chinese 1 Wh3, respectively. Lentiviral vectors containing the gra15(II) or rop16(I/III) plasmid were constructed and used to infect the RAW264.7 cell line. The polarization of the transfected cells was evaluated, followed by co-culture of the biased macrophages with mouse hepatic stellate JS1 cells. Then, mice were injected with GRA15(II)-driven macrophages via the tail vein and infected with S. japonicum cercariae. TgGRA15(II) induced a M1-biased response, whereas TgROP16(I/III) drove the macrophages to a M2-like phenotype. The in vitro experiments indicated that JS1 cell proliferation and collagen synthesis were decreased following co-culture with TgGRA15(II)-activated macrophages. Furthermore, mice inoculated with TgGRA15(II)-biased macrophages displayed a notable alleviation of collagen deposition and granuloma formation in their liver tissues. Our results suggest that TgGRA15(II)-induced M1 cells may dampen the M2 dominant pathogenesis of hepatic fibrosis and granulomatosis. These results provide insights into the use of parasite-derived immunomodulators as potential anti-fibrosis agents and to re-balance the schistosomiasis-induced immune response.