Investigation of how systemic viral infection influences disease course in mice expressing mutant human tau finds that dual PD-1/TIGIT blockade accelerates neurological dysfunction and identifies 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.
Abstract
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.
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.
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.
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.
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)
Neuroimmunology (NEUR)
Growing evidence suggests that peripheral infections contribute to neurodegenerative disease progression and cognitive impairment, yet the underlying neuro-immune mechanisms remain poorly understood.
Here, we used a mouse model of Influenza A virus (H1N1) respiratory infection to investigate immune responses in the central nervous system (CNS).
At day 6 post-infection, we observed significant increases in microglia, perivascular macrophages, monocytes, NK cells, and neutrophils, indicating infection-driven immune activation within the CNS. Strikingly, eosinophils persisted in both brain/leptomeninges and dura mater up to 7 weeks post-infection. No viral RNA was detected in the brain at any time point, whereas lung tissue harbored high viral loads, suggesting peripheral infection as the driver of neuroinflammation. Cytokine and chemokine profiling revealed persistent elevation of CCL11 in serum at both day 6 and week 7. CCL11 has been implicated in other peripheral infection related neuroinflammation, potentially contributing to myelin loss and impaired neurogenesis, although mechanisms remain unknown. To address the role of CCL11 in CNS inflammation and dysfunction in this context, we have begun characterizing CCL11 knockout (KO) mice following influenza infection. Preliminary results indicate that CCL11-KO mice are more susceptible to infection compared to controls, highlighting a complex role for CCL11 in balancing antiviral defense and neuroinflammation. Furthermore, scRNA-seq analysis of healthy mice revealed high CCL11 expression in dural sinus smooth muscle cells, leptomeningeal fibroblasts and brain pericytes suggesting that brain border cells may contribute to local regulation of immune responses after infection.
Moving forward, our goal is to investigate CCL11 as a potential mediator linking peripheral respiratory infection to persistent neuroinflammation, providing insight into mechanisms by which infections may contribute to long-term brain dysfunction.
Emerging pathogen consortia, HHMI
Neuroimmunology (NEUR)
Bristy Sabikunnahar, Lauren Dang, Beth Stevens et al.· Journal of Immunology· 0 citations
Introduction Parkinson’s disease (PD) is increasingly recognized as a neurological disorder characterized not only by neurodegeneration but also by chronic immune dysregulation across the lifespan. Although the initiating events underlying PD remain unclear, accumulating evidence suggests that inflammatory processes may contribute to disease susceptibility and progression. Mutations in leucine-rich repeat kinase 2 (LRRK2), particularly the gain-of-function G2019S variant, represent the common genetic cause of familial PD and have been implicated in immune regulation and infection susceptibility. To date, most research has focused on the effect of LRRK2 mutation in neurons and the contributions of G2019S-mediated kinase activity to neuronal toxicity, leaving the role of G2019S-mediated kinase activity in immune cell homeostasis and its contribution to PD pathogenesis largely unresolved. Methods Here, we used murine overexpression models of wildtype and G2019S variant of mouse Lrrk2 to examine how Lrrk2 G2019S shapes host defense across viral and bacterial infection models. We tested systemic sepsis and Escherichia coli infection to examine bacterial clearance. We followed up by testing macrophage responses to intracellular (Listeria monocytogenes) or primarily extracellular (Pseudomonas aeruginosa) bacteria. Finally, tested antibody-mediated immunity using influenza and cytotoxic T cell-mediated immunity using lymphocytic choriomeningitis virus (LCMV) infection. Results We found that Lrrk2 G2019S overexpression enhanced survival and bacterial clearance during P. aeruginosa lung infection, whereas the same genotype worsened outcomes in polymicrobial sepsis, with increased mortality, pulmonary myeloid infiltration and a hematopoietic cell-intrinsic phenotype. During L. monocytogenes infection, Lrrk2 G2019S selectively reduced non-classical monocytes without altering disease progression. In influenza and LCMV infection, G2019S altered antigen-specific CD8+ T cell distribution without major changes in cell memory responses clinical severity. Discussion Together, these data show that Lrrk2 G2019S selectively reprograms innate and adaptive immunity in a pathogen- and tissue-dependent manner, uncoupling inflammatory magnitude from effective host defense. These results and previous work support a model in which the G2019S LRRK2 variant contributes to maladaptive inflammatory responses to specific infection challenges, providing insight into how lifetime immune perturbations may intersect with genetic susceptibility to influence lifetime infection risk.
Andrea R. Merchak, Mary K. Herrick, M. Houser et al.· Frontiers in Cellular Neuros...· 0 citations
It is suggested that bidirectional disruptions to normal LRRK2 function break immune homeostasis and immune cell function should be carefully considered when targeting LRRK2 kinase activity in patients with PD.
Robert C. Sharp, Shannon C. Wall, Jordan C. Follet et al.· bioRxiv· 0 citations
Infections have long been implicated as causative factors in Alzheimer's disease (AD). Multiple studies have further suggested a key role for herpesviruses, such as cytomegalovirus (CMV). Using transgenic 3xTg-AD mice, we demonstrate that systemic infection with the β-herpesvirus murine CMV (MCMV) accelerates the development of cognitive decline, tauopathy and synaptic loss in the hippocampus, all of which are key features of AD. Accelerated disease progression after infection was associated with substantial lymphocyte infiltration into the brain, dominated by MCMV-specific effector memory CD8+ T cells expressing CXCR3. T cell receptor analyses revealed that clonally diverse virus-specific CD8+ T cells were selectively recruited into the brain during the development of AD. T cell depletion or treatment with the antiviral drug valganciclovir during chronic infection reduced lymphocytic infiltrates in the brain and reversed cognitive decline. These data provide a mechanistic link between chronic viral infections and the development of AD.
M. Marsden, J. McLaren, Ryan J Bevan et al.· Brain : a journal of neurolo...· 0 citations
Neurological and neuropsychiatric symptoms, collectively termed neuroPASC, are among the most prevalent Post-Acute Sequelae of COVID-19 (PASC). Neuroinflammation – particularly microglia reactivity – has been implicated in neuroPASC. We previously established a PASC model in which SARS-CoV-2-infected mice developed persistent behavior alterations and prolonged neuroinflammation for up to 120 days post-infection (dpi). Here, we extend these results to a longitudinal single-cell RNA sequencing analysis of brain immune cells collected at 0, 6, 30, and 100 dpi. We identify a coordinated contribution of infiltrating and resident myeloid cells to the initiation and persistence of neuroinflammation. In specific, microglia display sustained expansion of subclusters characterized by inflammatory, stress response, and metabolic signatures. Border-associated macrophages upregulate monocyte attractants during acute infection. Concurrently, peripherally derived monocytes and neutrophils mount transient inflammatory responses, potentially triggering long-term microglial reactivity. Together, these findings provide a high-resolution atlas of brain myeloid immune dynamics during neuroPASC and highlight a central role for microglia in sustaining chronic neuroinflammation. While prolonged neuroinflammation is considered a hallmark of Post Acute Sequelae of COVID-19 (PASC), its basis is poorly understood. The authors here manifest infiltration of peripheral myeloid cells during acute infection and prolonged microglial activation in mice with PASC, potentially contributing to neurological abnormalities.
Lu Tan, A. Verma, Shearon A. Lowery et al.· Nature Communications· 0 citations
ABSTRACT Powassan virus (POWV) causes lethal encephalitis in the elderly and long-term neurological sequelae in survivors. Mirroring human disease, POWV strain LI9 directs age-dependent lethality in C57BL/6 (B6) mice, resulting in spongiform encephalitis, gliosis, and inflammatory cytokine/chemokine responses in the CNS. However, the mechanisms underlying age-dependent lethality and persistent neurodegenerative disease in POWV survivors remain to be resolved. Here, we analyzed cellular CNS responses to POWV LI9 infection in young (10-week-old) and aged (50-week-old) mice using single-cell RNA sequencing. Infection of young mice resulted in inflammatory CNS infiltrates (NK, CD4/CD8 T cells, and monocytes) and interferon responses that coincide with peak viral burden. In contrast, the CNS of aged infected mice instead featured upregulated astrocyte and neuronal genes associated with neurodegenerative and Alzheimer’s disease pathways and the transition of homeostatic microglia to a Trem2–ApoE-linked disease-associated microglial transcriptional state. Histological analysis revealed that amyloid precursor protein (APP)/amyloid-β (Aβ) accumulated in the CNS following POWV infection and that POWV envelope protein and APP/Aβ were selectively localized within layers L5/L6 of the cerebral cortex. POWV kinetically increased perinuclear APP/Aβ accumulation during acute infection and was highly expressed in the CNS of POWV survivors. Our findings reveal that POWV triggers glial cell responses and a neurodegenerative disease-associated microglia program of Alzheimer’s-like APP/Aβ accumulation in mice, which is consistent with long-term neurological sequelae in human POWV survivors. IMPORTANCE Powassan virus (POWV) causes lethal encephalitis and long-term cognitive deficits in survivors. Using an age-dependent murine model, we reveal that POWV-infected young mice direct robust CNS inflammatory infiltrates associated with viral clearance, whereas aged mice exhibit impaired immune responses and a shift from homeostatic to neurodegenerative glial cell states. POWV prompted the induction of disease-associated microglia (DAM) and Trem2–ApoE axis transcriptional responses that are hallmarks of APP/amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD). Remarkably, POWV induced progressive APP/Aβ accumulation in young and aged mice that persisted in survivors after viral clearance. This suggests that POWV induces an APP/Aβ neurodegenerative process and provides a potential cause of long-term neurological sequelae observed in human POWV survivors. Our data suggest that POWV initiates or exacerbates AD-like neuropathology and further rationalizes investigating the role of APP/Aβ responses in other encephalitic viruses. Powassan virus (POWV) causes lethal encephalitis and long-term cognitive deficits in survivors. Using an age-dependent murine model, we reveal that POWV-infected young mice direct robust CNS inflammatory infiltrates associated with viral clearance, whereas aged mice exhibit impaired immune responses and a shift from homeostatic to neurodegenerative glial cell states. POWV prompted the induction of disease-associated microglia (DAM) and Trem2–ApoE axis transcriptional responses that are hallmarks of APP/amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD). Remarkably, POWV induced progressive APP/Aβ accumulation in young and aged mice that persisted in survivors after viral clearance. This suggests that POWV induces an APP/Aβ neurodegenerative process and provides a potential cause of long-term neurological sequelae observed in human POWV survivors. Our data suggest that POWV initiates or exacerbates AD-like neuropathology and further rationalizes investigating the role of APP/Aβ responses in other encephalitic viruses.
M. D. de Souza, M. Lindner, Megan Mladinich-Valenti et al.· mBio· 0 citations