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Journal Article Review Epublish 12 citations

PubMed: 37628830 DOI: 10.3390/ijms241612648

Long COVID as a Tauopathy: Of "Brain Fog" and "Fusogen Storms".

Int J Mol Sci 24(16)

Authors: Adonis Sfera, Leah Rahman, Carlos Manuel Zapata-Martín Del Campo, Zisis Kozlakidis

Affiliations

  • Paton State Hospital, 3102 Highland Ave, Patton, CA 92369, USA.
  • School of Behavioral Health, Loma Linda University, 11139 Anderson St. Loma Linda, CA 92350, USA.
  • Department of Psychiatry, University of California, Riverside 900 University Ave, Riverside, CA 92521, USA.
  • Department of Neuroscience, University of Oregon, 222 Huestis Hall, Eugene, OR 97401, USA.
  • Instituto National de Cardiologia, Juan Badiano 1, Belisario Domínguez Secc 16, Tlalpan, Ciudad de México 14080, Mexico.
  • International Agency for Research on Cancer, World Health Organization, 69000 Lyon, France.

Abstract

Long COVID, also called post-acute sequelae of SARS-CoV-2, is characterized by a multitude of lingering symptoms, including impaired cognition, that can last for many months. This symptom, often called "brain fog", affects the life quality of numerous individuals, increasing medical complications as well as healthcare expenditures. The etiopathogenesis of SARS-CoV-2-induced cognitive deficit is unclear, but the most likely cause is chronic inflammation maintained by a viral remnant thriving in select body reservoirs. These viral sanctuaries are likely comprised of fused, senescent cells, including microglia and astrocytes, that the pathogen can convert into neurotoxic phenotypes. Moreover, as the enteric nervous system contains neurons and glia, the virus likely lingers in the gastrointestinal tract as well, accounting for the intestinal symptoms of long COVID. Fusogens are proteins that can overcome the repulsive forces between cell membranes, allowing the virus to coalesce with host cells and enter the cytoplasm. In the intracellular compartment, the pathogen hijacks the actin cytoskeleton, fusing host cells with each other and engendering pathological syncytia. Cell-cell fusion enables the virus to infect the healthy neighboring cells. We surmise that syncytia formation drives cognitive impairment by facilitating the "seeding" of hyperphosphorylated Tau, documented in COVID-19. In our previous work, we hypothesized that the SARS-CoV-2 virus induces premature endothelial senescence, increasing the permeability of the intestinal and blood-brain barrier. This enables the migration of gastrointestinal tract microbes and/or their components into the host circulation, eventually reaching the brain where they may induce cognitive dysfunction. For example, translocated lipopolysaccharides or microbial DNA can induce Tau hyperphosphorylation, likely accounting for memory problems. In this perspective article, we examine the pathogenetic mechanisms and potential biomarkers of long COVID, including microbial cell-free DNA, interleukin 22, and phosphorylated Tau, as well as the beneficial effect of transcutaneous vagal nerve stimulation.

MeSH

Tauopathies, Accounting, Cellular Senescence, Dna, Neuroglia, Blood-Brain Barrier, Cognition Disorders, Gastrointestinal Tract, Giant Cells, Cognitive Dysfunction, Sars-Cov-2, Post-Acute Covid-19 Syndrome

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