Cross-kingdom metabolic regulation by a symbiotic virus: Transient viral microRNAs coordinate host metabolism and immune responses.
Abstract
Symbiotic microorganisms and endogenous viruses play fundamental roles in shaping host physiology, yet the non-coding RNA-mediated mechanisms underlying viral-driven metabolic reprogramming remain poorly understood. Here, we demonstrate a novel mechanism of cross-kingdom metabolic manipulation mediated by symbiotic viral microRNAs. Using the tobacco cutworm Spodoptera litura, its endoparasitoid wasp Snellenius manilae, and the wasp-associated bracovirus SmBV as a model system, we identified two virus-derived microRNAs, SmBV-miR-2733 and SmBV-miR-3772, that target the host lipogenic genes encoding AGPAT and lipin, leading to the suppression of glycerolipid biosynthesis and reduced lipid accumulation. Functional analyses revealed that these symbiotic viral miRNAs concurrently attenuate host innate immune signaling pathways (Toll and JAK/STAT) and cellular encapsulation, establishing a mechanistic link between viral metabolic coercion and host immunomodulation. Crucially, this viral microRNA-mediated regulation is transient and highly dynamic; miRNA expression declines during later stages of infection, coinciding with an intermediate recovery of host lipogenic gene expression and lipid reserves, which may help sustain the developing parasitoids. Prolonged experimental maintenance of viral miRNAs disrupted host energetic homeostasis and compromised symbiotic success, underscoring the evolutionary necessity of temporally coordinated metabolic regulation. Comparative genomic analysis identified miR-2733- and miR-3772-like candidate loci with miRNA-precursor-like structures that are unevenly distributed across related bracovirus lineages. Together, our findings provide significant mechanistic insights into how symbiotic viral effectors post-transcriptionally rewire host metabolic and immune networks, offering a broader conceptual framework for understanding homeostasis in diverse host-microbe symbioses.