Regulation of Host Regulatory T Cell Differentiation by emu‐let‐7‐5p in Echinococcus multilocularis Infection Through Targeting NFκB2

Regulatory T cells (Treg) play a crucial role in creating an immunosuppressive microenvironment surrounding the metacestode during chronic alveolar echinococcosis (AE). However, the mechanisms by which E. multilocularis induces Treg differentiation, particularly the role of parasite-derived microRNAs (miRNAs), remain largely unexplored. Here, we demonstrate that E. multilocularis can significantly induce the differentiation of Treg in mice. Emu-let-7-5p is upregulated in peripheral blood lymphocyte cells (PBLC) and splenic lymphocytes of E. multilocularis-infected mice. Exosomes enriched with emu-let-7-5p were found to upregulate the expressions of Treg markers. Conversely, exosomes collected following the knockdown of worm-derived emu-let-7-5p via RNA interference resulted in a reversal of Treg marker expression in PBLC. Mechanistically, emu-let-7-5p regulates Treg differentiation by targeting NFκB2. Knockdown of emu-let-7-5p in E. multilocularis-infected mice resulted in diminished Treg differentiation, leading to a significant reduction in worm load. These findings reveal that emu-let-7-5p drives Treg differentiation by suppressing NFκB2, representing a novel immune evasion strategy of E. multilocularis. Sustained inhibition of parasite-derived emu-let-7-5p may provide a therapeutic avenue for controlling AE progression.