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Dysregulated TFEB-autophagy-lysosome pathway links acute COVID-19 immunopathology to Long COVID sequelae

Magdalena Gabig-Cimińska1

  • 1Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Gdańsk, Poland.

Frontiers in Immunology
|December 15, 2025
PubMed

Insights

SARS-CoV-2 disrupts the autophagy-lysosome pathway (ALP), hindering viral clearance and causing inflammation. Restoring TFEB activity and ALP may combat viral persistence and Long COVID symptoms.

Area of Science:

  • Immunology
  • Cell Biology
  • Virology

Background:

  • SARS-CoV-2 disrupts cellular homeostasis, specifically the autophagy-lysosome pathway (ALP).
  • Viral proteins inhibit autophagosome-lysosome fusion, leading to incomplete autophagy, viral persistence, and hyperinflammation.
  • Transcription factor EB (TFEB) is a key regulator of lysosomal biogenesis and autophagy, influencing host immune responses.

Purpose of the Study:

  • To synthesize current knowledge on the TFEB-ALP axis in COVID-19 pathogenesis.
  • To highlight the role of TFEB and ALP in acute immunopathology and Long COVID.
  • To explore the therapeutic potential of targeting the TFEB-autophagy pathway.

Main Methods:

  • Literature review and synthesis of existing research on TFEB, ALP, and SARS-CoV-2.
  • Analysis of the molecular mechanisms by which SARS-CoV-2 interacts with the TFEB-ALP axis.
  • Evaluation of the implications for COVID-19 pathogenesis and potential therapeutic strategies.

Main Results:

  • SARS-CoV-2 subverts the ALP, impairing innate immunity and viral clearance.
  • TFEB plays a crucial role in regulating lysosomal function, autophagy, and immune responses during coronavirus infection.
  • Dysregulation of the TFEB-ALP axis contributes to both acute COVID-19 immunopathology and persistent Long COVID sequelae.

Conclusions:

  • Restoring TFEB activity and autophagic flux can counteract SARS-CoV-2 evasion and reduce inflammation.
  • Targeting the TFEB-autophagy pathway offers a promising host-directed therapeutic strategy for COVID-19.
  • This approach may help restore immune homeostasis, limit acute tissue damage, and mitigate Long COVID symptoms.
Keywords:
COVID-19Long COVIDSARS-CoV-2autophagy-lysosome pathway (ALP)host-directed therapylysosomal organelletranscription factor EB (TFEB)

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