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A Shift in SARS-CoV-2 Omicron Variant's Entry Pathway Might Explain Different Clinical Outcomes.

Calixto Machado-Curbelo1, Joel Gutiérrez-Gil1, Alina González-Quevedo1

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MEDICC Review
|November 23, 2022
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The Omicron variant of SARS-CoV-2 causes milder COVID-19, potentially by altering its entry into cells. This may reduce brainstem invasion, lessening severe respiratory issues and mechanical ventilation needs.

Keywords:
COVID-19COVID-19 pandemicsSARS-CoV-2ageusiaanosmiabrain stemcathepsinsendosomesolfactory nerverespiratory centersmelltaste

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Area of Science:

  • Virology
  • Pathogenesis
  • Epidemiology

Background:

  • The Omicron variant of SARS-CoV-2 has caused a surge in COVID-19 cases globally, characterized by less severe illness and reduced hospitalizations compared to previous variants.
  • Omicron's symptoms often resemble the common cold, with a notably lower incidence of loss of taste and smell, a hallmark of earlier SARS-CoV-2 infections.
  • Previous research suggests SARS-CoV-2 can invade the brainstem via olfactory nerves, potentially causing fatal respiratory distress syndrome (ARDS).

Purpose of the Study:

  • To investigate the potential impact of Omicron's altered cellular entry mechanism on its neurotropism and pathogenesis.
  • To hypothesize whether changes in SARS-CoV-2 entry pathway affect the virus's ability to invade the brainstem and cause severe respiratory complications.

Main Methods:

  • Comparative analysis of Omicron's cellular entry pathway (cathepsin-dependent endosomal fusion) versus previous variants (TMPRSS2-mediated cell-surface fusion).
  • Review of existing literature on SARS-CoV-2 neuroinvasion, olfactory pathways, and brainstem involvement in COVID-19 pathogenesis.
  • Hypothetical modeling of the consequences of altered viral entry on transsynaptic spread to the brainstem.

Main Results:

  • Omicron predominantly utilizes cathepsin-dependent endosomal fusion, differing from the TMPRSS2-mediated pathway of earlier variants.
  • This shift in entry mechanism may alter viral tropism and pathogenesis.
  • A potential consequence is reduced direct invasion of the brainstem via olfactory nerves.

Conclusions:

  • The altered entry pathway of the Omicron variant may decrease its neuroinvasive potential.
  • Reduced brainstem invasion could lead to diminished respiratory center dysfunction, thereby lowering the incidence of ARDS and the need for mechanical ventilation.
  • This hypothesis offers a potential explanation for the observed decrease in severe COVID-19 outcomes during the Omicron wave.