Systemic viral infection diversifies neurodegenerative disease progression 2310089

Abstract Introduction Environmental exposures across the lifespan shape the immune landscape and can influence responses to later challenges. Both innate and adaptive immunity affect the trajectory of neurodegenerative diseases. We have recently shown in mice that microglia slow tauopathy progression by limiting tau spread within the CNS and into the periphery, and that a granzyme K-expressing CD8+ T cell subset engages microglia to reduce microglial distress, restrict tau dissemination, and delay neurological decline in a PD-1/TIGIT-dependent manner. Similar microglia-T cell interactions were observed in human brains with tau-rich lesions associated with age, Alzheimer’s disease, or chronic traumatic encephalopathy. Here, we investigated how systemic viral infection influences disease course in mice expressing mutant human tau. Methods Single cell TCR sequencing, flow cytometry, immunofluorescence, and behavioral assessments were used to define immune changes and disease progression in P301S (Thy1a promoter) mice following systemic infection. Results We found that dual PD-1/TIGIT blockade accelerates neurological dysfunction. In contrast, intravenous LCMV Armstrong infection elicited robust peripheral immune activation yet did not alter the overall rate of decline in P301S mice; instead, it produced a marked increase in variability among individual disease trajectories. We further identified a tauopathy-specific surface marker signature that delineates a subset of Trm-like granzyme K+ CD8+ T cells in the CNS and draining lymph nodes that appears to slow disease progression. The heightened heterogeneity observed after viral infection suggests that systemic immune challenges may perturb this population in unpredictable ways. Conclusion These data demonstrate that tauopathy progression is highly sensitive to systemic immune perturbations, including non-neurotropic viral infections. They underscore the complexity of neurodegenerative disease and highlight how lifelong immunological challenges shape CNS pathology. Funding Source Intramural program at the National Institute of Neurological Disorders & Stroke and the National Institute of Allergy & Infectious Diseases, NIH Defense Health Agency (310286-1.00-65642 and 311661-5.00-66323) Topic Categories Neuroimmunology (NEUR)