Significance of Dementia and the Need to Explore Mechanistic Contributions of Viral Infection

Converging empirical evidence suggests that a higher lifetime infection burden is associated with cardiometabolic disease manifestations as well as with neurodegeneration and dementia. We and others have evidence that intermittent pathogen exposure, and presumably the immune response to this, impairs cognition, alters brain microvessel energy metabolism, induces neuroinflammation, and increases hippocampal blood-brain barrier permeability, which may in turn exacerbate Alzheimer’s phenotypes and stroke negative outcomes. What is still being discerned is the extent to which pathogen neurotropism is required for the realization of these negative nervous system manifestations and the mechanisms contributing to these. For this research program, in contributing knowledge regarding the brain and periphery impacts of cytomegalovirus exposure, we will explore the interaction between infection history, AD-and cardiometabolic-associated cascades, and both systemic and neuroinflammation. Our approach will use our newly developed intermittent infection model to measure viral impacts on hippocampal neuron structure, cardiometabolic function, and cognition as well as amyloid-beta plaque and neurofibrillary tangle accumulation in both normally aging mice and mice carrying genetic AD risk factor genes (Aim 1). We will also investigate transcriptional profile changes of infection in AD mice (Aim 2). Finally, we will evaluate the link that virus-induced T cell immune responses may have in driving viral-associated dementia-like cognitive and neurobiological dysfunction (Aim 3). This approach is innovative as a recurrent infection exposure regimen such as ours represents a departure from the scientific status quo in this field and more translationally mimics human systemic viral infection experience during adulthood. Further, it leverages cutting-edge spatial transcriptomics to comprehensively examine virus-induced transcriptomic profile shits at a sub-cellular level in brain and reveal new targets. Finally, this work links events impacting peripheral organ system with neurological consequences. This knowledge is essential to advance our understanding of the role that infections play in biological aging and neurodegenerative cascades. Our accomplished interdisciplinary research and mentoring team is well-poised to carry out the proposed studies. Successful completion of the aims could support interrogation of neural cell types vulnerable to the consequences of intermittent viral infection and will support implementation of a more translational mixed pathogen model. These effects are of keen interest to the TUTSI COBRE and to Louisiana residents, given the large health