Neuroinflammation: Spike Protein Priming and Null Results

1 Frank et al. 2024 β€” SARS-CoV-2 S1 Subunit Protracted Priming of Neuroinflammatory Responses

Full Citation:: Frank MG, Ball JB, Hopkins S, et al. SARS-CoV-2 S1 subunit produces a protracted priming of the neuroinflammatory, physiological, and behavioral responses to a remote immune challenge: A role for corticosteroids. Brain, Behavior, and Immunity. 2024;121:87–103. (Frank et al. 2024) DOI:: 10.1016/j.bbi.2024.07.034 PMID:: 39043345 Study Design:: Animal model (rat); S1 subunit administration followed one week later by LPS immune challenge Key Findings::

- Prior S1 exposure potentiates subsequent neuroinflammatory, physiological, and behavioral responses to LPS challenge
- S1 reduces baseline brain corticosteroid levels, disinhibiting innate immune activation
- Neuroinflammatory priming genes (MhcII$\alpha$, Nlrp3, Tlr4) remain upregulated in brain regions 7 days after S1 treatment
- S1 activates TLR2 and TLR4 β€” spike protein structural components function as PAMPs driving pattern-recognition signaling
- Provides mechanistic basis for why neuroinflammatory responses persist long after acute SARS-CoV-2 exposure

Relevance:: Directly relevant to ME/CFS and Long COVID neuroinflammation hypothesis. If S1 spike protein can prime brain innate immunity in a sustained manner via corticosteroid reduction and TLR4 upregulation, this could explain why patients report worsening neurological symptoms following any subsequent immune challenge (even minor infections), and why neuroinflammation persists in Long COVID without requiring ongoing viral replication. Certainty Assessment::

- *Quality:* Medium-High (Brain, Behavior, and Immunity; rigorous rodent model)
- *Sample:* Animal model β€” translational certainty pending human studies
- *Replication:* Consistent with independent in vitro S1 neuroinflammation studies
- *Certainty:* 0.55 (animal model; human translation inferential)
- *Limitation:* Rat model; does not demonstrate the same mechanism directly in human brain tissue

2 Omdal et al. 2026 β€” Long-COVID: No Neuronal Damage, Neuroinflammation, or Systemic Inflammation Detected in Circulating Markers

Full Citation:: Omdal R, Lenning OB, Jonsson G, et al. Long-COVID: assessment of circulating markers suggests no cerebral neuronal damage, neuroinflammation or systemic inflammation β€” a controlled study. Scientific Reports. 2026. (Omdal et al. 2026) DOI:: 10.1038/s41598-026-40142-0 Study Design:: Single-centre case-control (Stavanger University Hospital, Norway); age- and sex-matched Sample Size:: \(n=48\) long-COVID patients, \(n=48\) recovered controls; median 69 weeks post-infection Key Findings::

- No significant differences in neurofilament light (NfL) or GFAP between long-COVID and recovered controls
- Absence of neuroinflammation markers suggests ongoing neuronal injury is *not* required to maintain persistent long-COVID symptoms
- Standard circulating neuroinflammation biomarkers may be insufficient to detect the localized or tissue-based neuroinflammation seen in PET studies

Relevance:: Important negative result that constrains the neuroinflammation hypothesis. The absence of circulating NfL/GFAP elevation in long COVID at median 69 weeks does not rule out neuroinflammation, but indicates it is not accompanied by neuronal injury detectable in blood. This is consistent with the glial activation hypothesis (microglia/astrocyte activity without overt neurodegeneration) and underscores that PET imaging, not blood biomarkers, is the appropriate tool for detecting neuroinflammation in this context. Certainty Assessment::

- *Quality:* Medium (Scientific Reports; small matched cohort; single centre)
- *Sample:* $n=48$ per group
- *Replication:* Not yet independently replicated
- *Certainty:* 0.55 (solid null finding but limited by biomarker selection and single centre)
- *Limitation:* Circulating NfL/GFAP are markers of neuronal injury, not microglial activation β€” does not rule out glial neuroinflammation

References

Frank, Matthew G., Jayson B. Ball, Shelby Hopkins, Tel Kelley, Angelina J. Kuzma, Robert S. Thompson, Monika Fleshner, and Steven F. Maier. 2024. β€œSARS-CoV-2 S1 Subunit Produces a Protracted Priming of the Neuroinflammatory, Physiological, and Behavioral Responses to a Remote Immune Challenge: A Role for Corticosteroids.” Brain, Behavior, and Immunity 121: 87–103. https://doi.org/10.1016/j.bbi.2024.07.034.
Omdal, Roald, Ole Birger Lenning, GΓΈran Jonsson, et al. 2026. β€œLong-COVID: Assessment of Circulating Markers Suggests No Cerebral Neuronal Damage, Neuroinflammation or Systemic Inflammation β€” a Controlled Study.” Scientific Reports. https://doi.org/10.1038/s41598-026-40142-0.