Immune-mediated pathogenic mechanisms of Neuro-PASC in Veterans

Among the concerns of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the development of neurological manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC) or neuro- PASC. Research shows that neuropsychiatric impairments, including cognitive problems, depression, and anxiety are among the most common persistent symptoms (following fatigue), occurring in approximately 50%- 80% of individuals. In this Merit Review project, our multi-disciplinary team will test an overarching hypothesis that specific inflammatory factors [e.g., monokine induced by gamma interferon (MIG)], signaling pathways [e.g., interferon (IFN-)], genotypes (APOE4), and immunosuppressive cells contribute to the development and persistence of neuro-PASC. Our preliminary results and published studies provide rationale for the research. We found that individuals with neuro-PASC who experienced more severe COVID-19 have increased levels of circulating inflammatory factors [e.g., MIG, tumor necrosis factor-alpha (TNF-)] and report increased anxiety and depression, as compared to those with mild disease. Further, lower levels of cortisol, a stress hormone that helps the body control inflammation, have been observed in individuals with long COVID. In addition, carriers of the APOE4 genotype appear to be at greater risk for severe COVID-19 and PASC fatigue. Based on these and other findings, we hypothesize that inflammatory factors in the interferon (IFN)-signaling pathway will be positively associated with cognitive injury and severity of neuropsychiatric symptoms (including increased depression and anxiety). We also hypothesize that APOE genotype will modify the severity of neuro-PASC. We propose three specific aims to test these hypotheses: Aim 1 will monitor and evaluate neuro-PASC symptoms over time (baseline, 6 months and 12 months) and determine whether APOE genotype modulates severity of neuro-PASC. Neuropsychological evaluations will assess domains most relevant to neuro-PASC (e.g., learning and memory, attention/concentration, decision-making, and executive function). Mental health symptoms known to be induced by inflammation and developing as a result of COVID-19 will also be evaluated. APOE genotyping will be determined based on saliva or blood samples. Aim 2 will identify immune-related biomarkers associated with neuro-PASC symptoms. Saliva and blood (plasma and PBMCs) samples will be collected at three timepoints (baseline, 6 months, and 12 months) from Veterans with and without neuro-PASC. Samples will be analyzed using a combination of ELISAs, Luminex-based multiplex assays, and Olink proteomics. Aim 3 (exploratory) will assess neuroimaging correlates of neuro-PASC symptoms using whole brain voxel-based morphometry, diffusion-tensor imaging, and task-based and resting-state functional connectivity. To accomplish these aims, we have teamed up with East Tennessee VA collaborators who have unique resources (e.g., Long COVID registry, Olink proteomics) and diverse expertise (e.g., virology, infectious diseases) to accelerate the translation of our new advances and knowledge into clinical practice.