The Spike Protein, Ferritin and Long COVID: Additional Damage to the Microvasculature

The Spike Protein appears to induce massive release of iron from Ferritin, damaging the microvasculature much like after mini strokes.

Iron overload and free radical production in the CECs after TFI. (A) Brightfield photomicrographs of the hippocampal CA1 area after Perls iron staining following sham operation (Ctrl) or 0.5, 2, and 8 h following TFI. Scale bar, 50 µm. (B) Brightfield and fluorescence photomicrographs of adjacent hippocampal CA1 sections after Perls staining (top panel) or immunolabeling with EBA (bottom panel) 0.5 h after TFI. Arrowheads indicate iron overload in endothelial cells. Scale bar, 50 µm. (C) Superimposed images of fluorescence photomicrographs of hippocampal sections labeled with EBA and MitoTracker Red CM-H2XROs (MT, red), a mitochondrial free radical probe, 2 h after Ctrl or TFI, alone or with administration of DFO (200 mg/kg, s.c.) or Neu2000 (50 mg/kg; i.p.) immediately after reperfusion. Abbreviations: Endo, endothelium; SO, stratum oriens; SP, stratum pyramidale; SR, stratum radiatum. Scale bar, 50 µm.

I would like to discuss an additional mechanism of microvascular damage today that the Spike Protein may induce. This mechanism can also help to explain the neurological symptoms of Long COVID – and why it resembles post stroke conditions. This mechanism starts with – the Endothelium. Brain endothelial cells contain high amounts of Ferritin.

Brain endothelial cells contain relatively high amounts of ferritin, and hence serve as active reservoirs of iron (Burdo et al., 2004). Ferritin acts as an iron donor when exposed to metabolic conditions associated with ischemia that causes low oxygen tension, high levels of the superoxide anion, and acidosis (Bralet et al., 1992; Paul, 2000). Iron that is overloaded in CECs (cerebral endothelial cells) after TFI (transient forebrain ischemia) is likely released from ferritin. Excessive free iron then triggers free radical production by virtue of the Fenton reaction and the Haber-Weiss cycle. Iron-mediated free radical production significantly contributes to BBB opening as shown by sensitivity to DFO or Neu2000.

Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats
https://pmc.ncbi.nlm.nih.gov/articles/PMC3047193/

The above mentioned iron overload causes microvessel endothelial damage and opening of the blood brain barrier. This is a phenomenon that occurs post mini strokes.

Iron overload and mitochondrial free radical production were evident in the microvessel endothelium of the hippocampus before endothelial cell damage occurred. Administration of deferoxamine (DFO), an iron chelator, or Neu2000, an antioxidant, blocked free radical production and endothelial cell degeneration. Our findings suggest that iron overload and iron-mediated free radical production cause loss of tight junction proteins and degeneration of endothelial cells, opening of the BBB after TFI.

Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats
https://pmc.ncbi.nlm.nih.gov/articles/PMC3047193/

Why I find this important is that the Spike Protein is almost certainly implicated in precisely the same type of damage via precisely the same mechanism. First, let’s look at what administering the Spike Protein does to the mouse brain.

Here, we administered the SARS-CoV-2 spike protein S1 subunit intranasally to K18-hACE2 transgenic mice and quantified ferroptotic marker protein expression in four brain regions (hippocampus, prefrontal cortex, cerebellum, and olfactory bulb) at 2, 6, and 12 weeks post-administration, alongside ultrastructural assessment by transmission electron microscopy (TEM) that was limited to the hippocampus and prefrontal cortex. Two-way ANOVA revealed region- and time-dependent modulation of iron-handling, antioxidant, and lipid peroxidation markers. In the hippocampus, FPN1 was significantly increased at 2 weeks, while TFR1 showed a time-dependent pattern without significant week-specific differences. In the prefrontal cortex, DMT1 significantly increased at 2 weeks, and GPx4 showed an overall treatment effect with a trend of increase at 6 weeks. The cerebellum exhibited early increases in FPN1 and GPx4 and a delayed increase in MDA-conjugated proteins. In the olfactory bulb, FPN1 increased at 12 weeks, with GPx4 showing an overall treatment effect and an early trend of decrease. TEM identified ferroptosis-consistent features in the hippocampus and prefrontal cortex at all time points. These findings suggest that spike protein exposure may be associated with time-dependent and brain-region-specific alterations of ferroptosis-related markers.

SARS-CoV-2 Spike Protein Induces Time-Dependent and Brain-Region-Specific Alterations in Ferroptosis Markers: A Preliminary Study in K18-hACE2 Mice
https://pmc.ncbi.nlm.nih.gov/articles/PMC12897609/

The authors of the above study correctly attribute this damage to the Ferritin dysregulation caused by the virus. As only the Spike Protein was administered in the study, we may understand the origins of the following.

Iron dysregulation serves as a protective mechanism during the acute illness since iron is a transition metal that acts as a catalyst for reactions that require electron transfer [29], such as the RNA-dependent RNA polymerase [30]. SARS-CoV-2 utilizes this iron-containing enzyme to replicate and synthesize its viral RNA. To deprive the virus of this essential element, the body sequesters iron into ferritin [31]. However, excessive iron storage into ferritin could be detrimental if it triggers nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy [32]. Massive release of iron from ferritin generates oxidative stress and ferroptosis [20]. This state of acute iron dysregulation during COVID-19 illness manifests as high serum ferritin concentration and low serum iron content, signaling a worse outcome [33,34,35,36,37]. In addition, patients with moderate to severe COVID-19 who later developed post-COVID manifestations were found to have overexpression of monocyte iron homeostasis genes [38].

SARS-CoV-2 Spike Protein Induces Time-Dependent and Brain-Region-Specific Alterations in Ferroptosis Markers: A Preliminary Study in K18-hACE2 Mice
https://pmc.ncbi.nlm.nih.gov/articles/PMC12897609/

What is also extremely interesting is that this upregulation of Ferritin is corelated to microvascular complications in Type 1 Diabetes. This suggests a systemic condition when examined in the context of the Spike Protein.

Serum ferritin levels were significantly higher in patients with T1DM in both groups compared with healthy controls (p < 0.001). Additionally, patients with microvascular complications had higher serum ferritin concentrations than those without microvascular complications (p < 0.001). Patients with microalbuminuria showed higher ferritin levels compared with patients without microalbuminuria (p < 0.05). Stepwise regression analysis revealed that levels of HbA1c and urinary albumin excretion were independently related to ferritin levels (p < 0.001 for both). On receiver operating characteristic (ROC) curve analysis, a ferritin cutoff value of 163.6 ng/mL differentiated patients with microvascular complications from those without microvascular complications with a sensitivity of 92.1% and specificity of 93.4%.

Ferritin levels in children and adolescents with type 1 diabetes mellitus: relationship with microvascular complications and glycemic control
https://www.aem-sbem.com/article/ferritin-levels-in-children-and-adolescents-with-type-1-diabetes-mellitus-relationship-with-microvascular-complications-and-glycemic-control/

Furthermore, the same upregulation is found in patients with NAFLD that have vascular damage.

Vascular damage was evaluated by common carotid arteries intima-media thickness (CC-IMT) measurement and plaque detection by ecocolor-doppler ultrasonography in 506 patients with clinical and ultrasonographic diagnosis of NAFLD, HFE mutations by restriction analysis in 342 patients. Serum hepcidin-25 was measured by time-of-flight mass spectrometry in 143 patients. At multivariate analysis CC-IMT was associated with systolic blood pressure, glucose, LDL cholesterol, abdominal circumference, age, and ferritin (p=0.048). Carotid plaques were independently associated with age, ferritin (p=0.0004), glucose, and hypertension. Ferritin reflected iron stores and metabolic syndrome components, but not inflammation or liver damage. Hyperferritinemia was associated with increased vascular damage only in patients with HFE genotypes associated with hepcidin upregulation by iron stores (p<0.0001), and serum hepcidin-25 was independently associated with carotid plaques (p=0.05).

Serum Ferritin Levels Are Associated with Vascular Damage in Patients with Nonalcoholic Fatty Liver Disease.
https://ashpublications.org/blood/article/114/22/5098/77164/Serum-Ferritin-Levels-Are-Associated-with-Vascular

We can now hypothesize that in addition to a direct attack on the Endothelium, the Spike Protein also induces other mechanisms that damage the microvasculature. It can also explain why Long COVID resembles a post stroke condition. And why the neurological symptoms are so heterogenous – it depends on what parts of the brain have been more affected.

Left Side

• Speech/language problems

• Abstract thinking

• Problems with thinking and memory

• Slow, cautious behavioral style

Right Side

• Vision problems

• Spatial thinking or imagery

• Problems with thinking and memory Quick, inquisitive behavioral style

Effects of Stroke
https://www.stroke.org/en/about-stroke/effects-of-stroke

To bring this all together, high Ferritin was found in those who experienced Brain Fog well after COVID.

We focused on serum ferritin levels in this study and collected information on the onset of Brain Fog through questionnaires and found that high ferritin levels during hospitalization were associated with the occurrence of Brain Fog. In addition, we excluded confounders as far as possible using propensity score analyses and found that ferritin was independently associated with Brain Fog in most of the models. We conducted phase analysis and evaluated the interaction of each phase with ferritin levels and Brain Fog. We found a positive correlation between serum ferritin levels during hospitalization and Brain Fog after COVID-19. High ferritin levels in patients with Brain Fog may reflect the contribution of chronic inflammation in the development of Brain Fog. This study provides a novel insight into the pathogenic mechanism of Brain Fog after COVID-19.

Serum ferritin level during hospitalization is associated with Brain Fog after COVID-19
https://www.nature.com/articles/s41598-023-40011-0

Mediating Ferritin may prove to be helpful to those suffering from Long COVID. I will continue to research this and report back to you. Please have a blessed week.

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