The expanding spectrum of infectious risk organisms and immunogenetic susceptibility in neuropsychiatric disorders

The spectrum of infectious risk organisms showing associations with psychiatric traits is expanding. Infectious agents can modulate the risk of psychiatric disorders at different stages of life, such as gestational, childhood, adolescent, and adult periods. Prenatal infection appears to ‘prime’ the developing brain, whereas infection during childhood or later periods may act as a ‘second hit’, and these may have synergistic effects on the risk of developing psychiatric diseases. However, neither all the individuals with antecedent infection develop psychiatric disorders, nor do infectious organisms alone lead to psychiatric phenotypes. This suggests modulatory effects of additional host factors. The host genetic background crucially determines differential susceptibility to infection and serves as an important gateway for immune activation and signalling, as well as homeostatic brain functions. Despite the presence of several immune checkpoints and effectors, the infectious organisms disrupt the balance between immune-activating and immune-compensatory mechanisms and contribute to immune dysregulation. This depends substantially on genetic loci encoding immune molecules such as Toll-like receptors, Major Histocompatibility Complex, cytokines/ chemokines and their receptors, complement proteins, and other molecules and elements such as human endogenous retroviruses and gut microbiome that have distinct roles in immune regulation and immune effector functions. Genetic variations within these loci not only influence differential susceptibility to infection but also confer risk to psychiatric disorders. This article highlights a comprehensive overview of the nexus between infections and immune function-related genes and their impact on psychiatric traits. Understanding such interactions will lead to the identification of genetic markers of susceptibility to infection and psychiatric diseases.