Sniffer restricts arboviral brain infections by regulating ROS levels and protecting blood-brain barrier integrity in Drosophila and mosquitoes

Arthropod-borne viruses (arboviruses) are transmitted to humans by arthropod vectors and pose a serious threat to global public health. Neurotropic arboviruses including Sindbis virus (SINV) persistently infect the central nervous system (CNS) of vector insects without causing notable pathological changes or affecting their behavior or lifespan. However, the mechanisms by which vector insects evade these viral infections in the brains are poorly understood. In this study, we found that loss of the carbonyl reductase Sniffer (Sni) led to a significant increase in SINV infection in the Drosophila brain. Sni regulates reactive oxygen species (ROS) levels, and its depletion leads to elevated ROS, which in turn disrupts the septate junctions (SJs) between subperineurial glia (SPG) cells, compromising the integrity and barrier function of the blood-brain barrier (BBB). Genetic and pharmacological reduction of ROS restored BBB integrity and reduced viral load in the brains of Sni-depleted flies. Additionally, we identified Sni homologs and revealed that the antiviral function of Sni is highly conserved in mosquitoes, where it regulates ROS and protects BBB integrity. Our results revealed an evolutionarily conserved antiviral mechanism in which Sni acts as an antioxidant that protects BBB integrity and restricts viral infection in the vector insect brain.