Systematic discovery of virus-perturbed molecular pathways linking to schizophrenia

Abstract

<p><b>V</b>irus infections increase risk of psychiatric disorders. Immune activation-mediated perturbation of cellular function is currently proposed as a potential mechanism. Here, we report an alternative mechanism: viral protein-mediated perturbation of molecular pathways. We collected high-quality interactions between human proteins and proteins of neurotrophic viruses, and found that viral targets were enriched with candidate genes of psychiatric disorders, such as schizophrenia (SCZ) and autism spectrum disorder. The viral targets were further mapped onto a high-quality protein interaction network for SCZ (the SCZ Network), and the viral proteins tend to bind hub proteins in the network, suggesting that viral proteins may perturb molecular pathways involved in SCZ. Both immune genes and non-immune genes in this network are likely to be targets of viral proteins, suggesting that the viral infection may lead to SCZ via perturbing immune and nonimmune functions. Using pull-downs coupled with mass spectrometry, 96 human proteins were identified to interact with HIV-1 Vpr. These HIV-1 Vpr targets are enriched with proteins encoded by SCZ candidate genes. AAVs carrying HIV-1 Vpr were stereotactically injected into the prefrontal cortex of mice, and the mice with HIV-1 Vpr expression displayed impairments in object recognition and enhanced anxiety. These results suggest that viruses infecting the brain cells may interfere with cellular functions of the brain through interactions between viral proteins and host proteins.</p>