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

## TL;DR

This study explores how arboviruses interact with mosquito cells, revealing a new role for the Brahma complex in viral replication.

## Contribution

The study identifies the chromatin-remodeling Brahma complex as a proviral host factor in arbovirus replication in mosquitoes.

## Key findings

- A multiomic analysis identified 110 novel host proteins interacting with arboviral capsids.
- The Brahma complex was found to support orthoflavivirus replication in mosquito cells.
- Arboviral capsids were shown to modulate chromatin accessibility in mosquitoes.

## Abstract

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.

•Virus-host interaction network of 11 arboviral capsids in mosquito cells.•Identification of novel host-dependency factors for DENV, LACV, and WNV.•Novel role of the chromatin-remodeling Brahma complex in orthoflavivirus replication.•Discovery of capsid-mediated transcriptional regulation in mosquito cells.

Virus-host interaction network of 11 arboviral capsids in mosquito cells.

Identification of novel host-dependency factors for DENV, LACV, and WNV.

Novel role of the chromatin-remodeling Brahma complex in orthoflavivirus replication.

Discovery of capsid-mediated transcriptional regulation in mosquito cells.

This study by Flory et al. characterizes virus–vector interactions in Aedes mosquito cells through a systematic proteomics-based survey of capsid interactors of 11 pathogenic arboviruses. In a dsRNA-based knockdown screen, the functional relevance of 110 capsid interactors was tested for three different arboviruses revealing several new host dependency factors. This study identified and characterized the novel mosquito host dependency factor, the chromatin-remodeling Brahma complex, and showed capsid-mediated transcriptional regulation activities using a multiomics sequencing approach.