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bioRxiv · 10.64898/2026.06.17.733010

SARS-CoV-2 S1 spike protein induces a temporal systemic immune response and promotes long-term anxiety-like behaviors

Merino-Galan, L.·Hemenway, J.·Jagana, H.·Jackson, T.·Rajendran, A.·Khanna, A.·Ortiz-Espinosa, S.·Sarkar, S.·Kalia, V.·Pattwell, S.
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Abstract

The SARS-CoV-2 S1 protein is associated with immune cell activation and persistent neurological symptoms, yet the underlying mechanisms remain unclear, posing a major challenge in elucidating Long COVID pathophysiology. To investigate how circulating S1 contributes to long-term neurological alterations, we intravenously injected hACE2 mice with varying doses of S1 (5, 10, and 20 {micro}g) and observed temporally dysregulated systemic inflammatory responses accompanied by sub-acute CD4+ T cell infiltration into central limbic regions. This immune response induced mild sustained increases in cFos+ cells in the amygdala and mild neuroinflammation in the hippocampal CA1 region, resulting in both acute and long-term anxiety-like behaviors, while working memory remained unaffected. Together, these findings suggest that systemic S1 protein induces a sustained proinflammatory response that promotes lasting neurological alterations through immune-to-brain signaling pathways. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/733010v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@10982caorg.highwire.dtl.DTLVardef@169a275org.highwire.dtl.DTLVardef@28e66aorg.highwire.dtl.DTLVardef@12f6c85_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Merino-Galan, L., Hemenway, J., Jagana, H., Jackson, T., Rajendran, A., Khanna, A., Ortiz-Espinosa, S., Sarkar, S., Kalia, V., Pattwell, S.. 2026-06-18. SARS-CoV-2 S1 spike protein induces a temporal systemic immune response and promotes long-term anxiety-like behaviors. https://doi.org/10.64898/2026.06.17.733010

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