Antiviral responses of Aedes mosquitoes to Old World alphaviruses

Aedes (Ae.) aegypti and Ae. albopictus are efficient vectors of medically important Old World alphaviruses including chikungunya virus. In contrast to the well-characterized responses to orthoflavivirus infections, antiviral defense against alphaviruses in Aedes mosquitoes remains comparatively underexplored. This review summarizes current knowledge of antiviral defense mechanisms in Ae. aegypti and Ae. albopictus, integrating insights from both intrinsic immune responses and extrinsic antiviral factors to translational relevance. RNA interference (RNAi) dominates the antiviral defense against alphaviruses, whereas canonical immune signaling pathways, including Toll, IMD, JAK/STAT and JNK demonstrate relatively limited, transient or species-specific activity. To establish persistent infections, alphaviruses have developed various immune evasion strategies, such as the expression of viral suppressors of RNAi (VSRs) as an RNAi counter-mechanism. Beyond acute antiviral responses, piRNAs derived from viral-derived DNA (vDNA) and endogenous viral elements (EVE) have been proposed to contribute to long-term immune memory. In addition to intrinsic immune defenses, superinfection exclusion and Wolbachia infection further shape vector competence to alphaviruses. Together, this review describes RNAi as the central defense relative to the context-dependent canonical signaling pathways, extrinsic factors to influence vector competence such as microbial interaction and superinfection exclusion, and highlights key concepts and challenges necessary for designing effective and sustainable arbovirus control strategies.