Multiomics Analysis of Arboviral Capsid Targets in Mosquitoes Reveals a Proviral Function of the Chromatin-Remodeling Brahma Complex

In recent years, arboviral infections have surged dramatically because of the geographic expansion of Aedes and Culex mosquitoes, their main vector mosquitoes. Despite significant efforts to uncover arbovirus-host interactions and viral protein effector functions in mammals, systematic studies aiming to characterize virus-vector interactions in arthropods are largely missing, and the functions and cellular targets of many arboviral proteins in mosquitoes remain elusive. Here, we applied a multiomic approach to systematically evaluate the ability of arboviral capsids to interact with the Aedes aegypti proteome. This extensive multimodal atlas across 11 pathogenic arboviral species spanning three viral genera revealed shared and distinct host factor specificities, uncovering species-, genus-, and vector preference-specific patterns of host usage in mosquitoes. Functional phenotypic screening of 110 newly discovered host proteins across three prototypic arboviruses (La Crosse virus, dengue virus, and West Nile virus) identified several novel host dependency factors, including a new role for the chromatin-remodeling Brahma complex in orthoflavivirus replication. Using a combination of biochemical and sequencing approaches, we characterized the cellular determinants of these interactions and profiled their functional consequences on the chromatin landscape. Altogether, this study provides a multilayered repository to categorize and characterize arboviral capsid effector functions in invertebrates, providing important cues on novel mechanisms of transcriptional regulation via capsid-mediated modulation of chromatin accessibility in insects.