Shin

• Telomere attrition: some pathogens integrate near telomeres or accelerate their shortening.

• Cognitive decline: viral proteins can seed amyloid or tau and activate neuroinflammation.

• Inflammaging: persistent cytokine and chemokine activation drives chronic low-grade inflammation.

• Cellular senescence: infections trigger senescence pathways that amplify inflammatory signaling.

• Immunosenescence and exhaustion: long-term immune stimulation pushes the system toward dysfunction.

• Epigenetic alterations: pathogens induce shifts in methylation and gene expression.

• Mitochondrial dysfunction: pathogens hijack mitochondrial signaling, use ROS, or exploit lipid droplets for replication.

• Microbiome dysbiosis: chronic infection destabilizes microbial communities and disrupts immune–metabolic crosstalk.

A recent review by Proal & VanElzakker (2025) outlines how chronic infections—whether viral, bacterial, fungal, or parasitic—can accelerate nearly every aspect of aging:

Two main breakthrough findings from this new Cell paper:

1. In cognitively healthy adults: shingles vaccination reduced incident MCI.

2. In people already diagnosed with dementia: shingles vaccination reduced deaths due to dementia and all-cause mortality.

But as far as I know, we don’t yet have a study showing mast cell-mediated disruption of the brainstem or its connective tissues in long COVID specifically (or its related conditions like fibromyalgia or ME/CFS). So while it's a plausible idea, I think future studies still need to demonstrate it.

Thanks for sharing that preprint and your idea. The experimental evidence for autoimmune-driven mast-cell activation is indeed relevant. Mast cells can influence connective-tissue structures around the brain, so the hypothesis makes biological sense.

2. IgG didn’t enter the brain and did not reproduce cognitive deficit, anxiety, or depression in mice, suggesting that cognitive/mental long COVID may involve mechanisms other than IgG autoantibodies.

1. No single antigen was identified. The autoimmunity appears heterogeneous rather than driven by one dominant antibody.

But there are two main mechanistic caveats:

This is one of the strongest demonstrations to date that long COVID pain can be antibody-mediated “autoimmune pain.”

The autoantibodies bind to sensory neurons in the dorsal root ganglia—not the brain—and trigger neuropathic pain. When IgG was removed or enzymatically digested, the pain response disappeared.

New preprint from Belgium: IgG antibodies from neuro-long COVID patients can directly induce pain behaviors when transferred into mice.

A recent Cell Reports report found that phosphorylated tau — usually cast as the villain — actually protects neurons by suppressing HSV-1 proteins via the cGAS-STING-TBK1 innate immune pathway. In infected neurons, p-tau cut viral protein expression and cell death from 64% to 7%.

The Quest to Eradicate Multiple Sclerosis with Epstein-Barr Virus (EBV) Vaccine It might even reduce the risk of some cancers, autoimmune diseases, and chronic fatigue syndromes as well.

Read more here: theinfectedneuron.substack.com/p/eradicate-...

Better yet, some of these candidates are being tested in clinical trials to address the long-term sequelae of EBV infection:

- Moderna mRNA-1195 for multiple sclerosis.
- EBViously EBV-001 for multiple sclerosis, certain cancers, and even ME/CFS.
- British and HK MVA-EL for certain cancers.

While we don't have a licensed EBV vaccine yet, several vaccine candidates are currently in development:

- mRNA vaccine by Moderna
- Nanoparticle vaccine by the NIH
- VLP vaccine by EBViously
- Viral vector vaccine by UK and Hong Kong scientists

Figure source: Dai et al. (2025), Viruses

Epstein–Barr virus (EBV) infection is linked to several chronic diseases in a causal manner, e.g.,

- Multiple sclerosis
- Lupus
- Nasopharyngeal cancer
- Stomach cancer
- Lymphoma

This begs the question: Where’s our EBV vaccine?

Figure source: Rzymski and Szuster-Ciesielska (2023), Reumatologia.

Imagine telling future neurologists that multiple sclerosis once affected millions, before we vaccinated against the virus that caused it.

theinfectedneuron.substack.com/p/eradicate-...

5. The big picture: there’s a shared mechanism of post-viral brain injury, which explains why different viruses can lead to overlapping chronic neurological symptoms.

4. But the field still has major gaps: few longitudinal studies, limited biomarkers, and no targeted therapies.

3. Viral CNS infections often leave lasting structural injury, including neuronal loss, synaptic dysfunction, and disrupted white matter.

2. Across viruses, the same signature appears: persistent neuroinflammation and primed microglia long after the virus is gone.

1. Up to 50% of people who survive viral CNS infections develop long-term neurological or psychiatric sequelae, such as cognitive decline, memory loss, fatigue, mood disorders, and even personality change.

Google Scholar notified me that a new review, “Sequelae of viral CNS infections including outcomes, mechanisms, and knowledge gaps,” cited one of my papers.

After going through it, here are the key points:

5. The big picture: there’s a shared mechanism of post-viral brain injury, which explains why different viruses can lead to overlapping chronic neurological symptoms.

4. But the field still has major gaps: few longitudinal studies, limited biomarkers, and no targeted therapies.

3. Viral CNS infections often leave lasting structural injury, including neuronal loss, synaptic dysfunction, and disrupted white matter.

2. Across viruses, the same signature appears: persistent neuroinflammation and primed microglia long after the virus is gone.