Rhododendron mariae Hance protects against dengue virus infection by targeting viral entry and modulating host-pathogen interactions.

Dengue virus (DENV) infection continues to pose a significant global public health threat, driven by complex host-pathogen dynamics and the absence of specific therapeutics. Rhododendron mariae Hance, a traditional medicinal herb from the Lingnan region of China, is historically recognized for its "warm nature" and "pungent taste," attributes traditionally linked to restoring host homeostasis and eliminating pathogens. Its potential to modulate host defenses against viral infections, however, remains largely unexplored. This study evaluated the polypharmacological anti-DENV properties of the ethanol extract of Rhododendron mariae Hance (RH). Chemical constituents were characterized using LC-MS/MS. In vitro assays assessed the protective effects of RH against DENV-2 across multiple cell lines via plaque assays, Western blot, and immunofluorescence. In vivo, a DENV-infected suckling mouse model was employed to examine the systemic effects of RH on viral clearance, tissue pathology, and host survival. LC-MS/MS profiling identified 19 bioactive compounds, including flavonoids (quercetin, astilbin, naringenin) and terpenoids, with documented immunomodulatory and anti-inflammatory activities. RH markedly inhibited progeny virus production and attenuated infection-induced cytopathic effects. Mechanistic analysis indicated that RH functioned as a host-directed barrier, disrupting DENV-2 interaction with host cells. In vivo administration of RH significantly mitigated infection-related systemic weight loss, improved clinical outcomes, reduced viral loads in key immune and organs (spleen and brain), suppressed brain pathology, and prolonged survival. These findings demonstrate that RH exerts anti-DENV activity by blocking viral entry and limiting infection-induced tissue damage. The observed reduction of viral burden in the spleen-a central immune organ-suggests a modulatory effect on the infection microenvironment. This study establishes a scientific basis for developing RH as a next-generation immunomodulatory and anti-infective agent, integrating traditional botanical knowledge with modern host-directed strategies for flavivirus control.