Schistosoma japonicum extracellular vesicle miRNA cargo regulates host macrophage functions facilitating parasitism

Schistosome infection persists for decades. Parasites are in close contact with host peripheral blood immune cells, yet little is known about the regulatory interactions between parasites and these immune cells. Here, we report that extracellular vesicles (EVs) released from Schistosoma japonicum are taken up primarily by macrophages and other host peripheral blood immune cells and their miRNA cargo transferred into recipient cells. Uptake of S. japonicum EV miR-125b and bantam miRNAs into host cells increased macrophage proliferation and TNF-alpha production by regulating the corresponding targets including Pros1, Fam212b, and Clmp. Mice infected with S. japonicum exhibit an increased population of monocytes and elevated levels of TNF-alpha. Reduction of host monocytes and TNF-alpha level in S. japonicum infected mice led to a significant reduction in worm and egg burden and pathology. Overall, we demonstrate that S. japonicum EV miRNAs can regulate host macrophages illustrating parasite modulation of the host immune response to facilitate parasite survival. Our findings provide valuable insights into the schistosome-host interaction which may help to develop novel intervention strategies against schistosomiasis. Author summary Schistosomes that cause schistosomiasis infection persist for decades despite a host immune response. Therefore, elucidating the mechanism of schistosome survival will not only contribute to the understanding of host-parasite interaction but also lead to the development of novel strategies against schistosomiasis. Extracellular vesicles (EVs) and their miRNA cargo have been shown to be mediators of intercellular communication involved in the regulation of many biological processes. Here, we demonstrated that EVs released from Schistosoma japonicum (SjEVs) are taken up primarily by macrophages and other host peripheral blood immune cells and their miRNA cargo transferred into recipient cells. Uptake of S. japonicum EV miR-125b and bantam miRNAs into host cells increased macrophage proliferation and TNF-alpha production that contributes to parasite survival. Our findings reveal key roles of SjEV miRNAs for facilitating parasitism in schistosomes.