The structural and functional significance of Aedes aegypti AgBR1 flavivirus immunomodulator

Zika virus, an arbovirus, relies on mosquitoes as vectors for its spread and transmission. During blood feeding mosquitoes inoculate saliva containing various proteins. Recently, AgBR1, an Aedes aegypti salivary gland protein, has garnered attention for its immunomodulatory viral activity, along with another protein, NeSt1. We have solved the crystal structure of AgBR1, whose chitinase fold has been repurposed, likely to help blood feeding. We show that AgBR1 and NeSt1, when present in murine macrophages, alter functional cellular pathways related to virus entry by endocytosis, immune response, and cell proliferation. AgBR1 (and NeSt1) do not directly bind to the Zika virus or modulate its replication. In this light, we suggest that their immunomodulatory activity on Zika transmission is through the modulation of host-cell response, likely a consequence of evolutionary crosstalk and virus opportunism. Our structural and functional insights are prerequisites for developing strategies to halt the spread of mosquito-borne disease.