A pathogen-derived small RNA modulates host immunity for chronic parasitism

Parasites that rely on prolonged host exploitation must balance immune evasion with host survival. The entomopathogenic fungus Ophiocordyceps sinensis maintains its insect host, Thitarodes xiaojinensis, for months before host death, but the mechanisms stabilizing host immunity during this period are unclear. Here, we identify a cross-kingdom regulatory strategy mediated by a fungal microRNA-like RNA (milRNA), Os-milRNA2, which is delivered into host immune tissues and directly targets the antimicrobial peptide gene attacin-1. Os-milRNA2 accumulates during mid-stage infection, repressing immune gene expression, whereas its inhibition restores host immunity and restricts fungal proliferation. Comparative analyses reveal lineage-specific retention of the Os-milRNA2 binding site in the T. xiaojinensis 3’UTR of attacin-1, indicating regulatory coevolution. Our findings show that a slow-killing parasite attenuates specific immune effectors to maintain host-pathogen homeostasis during chronic infection.