Cytomegalovirus, Brain Alterations, and Depression: Decoding Neuroinflammatory Pathways for Effective Intervention - PROJECT ABSTRACT/SUMMARY Depression affects at least one in every six people, and identifying targetable risk factors is urgently needed to facilitate early intervention and prevention. The literature and the applicant's pilot studies suggesting the neurotropic herpes virus, such as cytomegalovirus (CMV) infection, is capable of inducing neuroinflammation, which has been established as an important factor that contributes to the development of depression in vulnerable individuals. The objective for the proposed K01 award is to use CMV infection as a model to develop a comprehensive understanding that CMV infection-associated neuroinflammatory mechanism predicts disruption of frontotemporal circuitry and increased odds of depression. The applicant will use a multifaceted approach to understand the potential neurobiological pathways that may increase the risk of depression in individuals with CMV infection. This approach includes the use of existing blood-based serological markers to determine CMV serostatus and antibody levels, diffusion-weighted neuroimaging to assess brain microstructure integrity, polygenic score methods to prove host anti-CMV immunity, and behavioral assessments to identify depression cases and matched controls, as well as depressive symptoms, within the UK Biobank dataset. The proposed research aims to: (1) determine the associations between CMV seropositivity, brain alterations, and depression using the largest serological sample so far; (2) investigate links between genetic predisposition to CMV seropositivity, brain alterations, and depression; and (3) explore genetically predicted inflammatory molecular pathways through which CMV infection may affect brain integrity and depressive symptoms. This study will employ rigorous methods to elucidate the role of CMV in brain alteration and depression, which can lead to an actionable target to mitigate neuroinflammation and reduce depression risk. The innovative approach leverages polygenic scores to capture individual genetic differences in host immunity, offering an opportunity to identify at-risk individuals and investigate the inflammatory mechanisms involved. This Career Development Award builds upon the applicant's neuroimaging expertise and prior research focus, and further provides training to: (1) bridge the knowledge gap on viral epidemiology in the context of mental health; (2) refine the understanding of the disrupted brain circuits and their relationship with the clinical symptoms of inflammation-associated depression; (3) apply statistical genetics to probe individual differences in immunity; and (4) develop professional skills and transition to independence. The proposed research and training will be mentored by a team of leading experts with diverse, complementary expertise, ensuring successful outcomes. Upon completion of this award, the applicant will be well-prepared for an independent research career in population immunopsychiatry, focusing to (1) gain a mechanistic understanding of how neurotropic viral infection may confer risk for mood disorders; and (2) determine which specific individuals are at risk for depression across the lifespan and the mechanisms of why they are at risk.
