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Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2

Marianne R Spalinger1, Golshid Sanati2, Pritha Chatterjee2

  • 1Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California; Department of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland.

Cellular and Molecular Gastroenterology and Hepatology
|January 5, 2025
PubMed

Insights

The autoimmune risk gene PTPN2 increases susceptibility to SARS-CoV-2 by promoting ACE2 receptor expression. This enhanced viral entry can be mitigated by the Janus kinase inhibitor tofacitinib.

Area of Science:

  • Immunology
  • Virology
  • Genetics

Background:

  • Severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2) caused a global pandemic with significant health and economic impacts.
  • Host factors influencing SARS-CoV-2 susceptibility and severe disease remain largely unknown, particularly in individuals with autoimmune/inflammatory disorders.

Purpose of the Study:

  • To investigate the role of the autoimmunity risk gene PTPN2 in SARS-CoV-2 viral uptake.
  • To determine if PTPN2 affects the expression of the SARS-CoV-2 receptor, angiotensin converting enzyme 2 (ACE2).

Main Methods:

  • Analysis of PTPN2 genotyped inflammatory bowel disease patients and PTPN2-deficient mice.
  • Investigation of PTPN2's effect on ACE2 expression in human intestinal and lung epithelial cells.
  • Assessment of virus-like particle and live SARS-CoV-2 uptake in relation to PTPN2 status.

Main Results:

  • A PTPN2 loss-of-function variant (rs1893217) was found to promote ACE2 expression.
  • This variant increased cellular entry of SARS-CoV-2 spike protein and live virus.
  • Elevated ACE2 expression and viral entry were linked to increased Janus kinase-signal transducers and activators of transcription signaling, and reversed by tofacitinib.

Conclusions:

  • The study identifies a novel risk biomarker associated with increased SARS-CoV-2 receptor expression and viral entry.
  • Findings suggest a potential therapeutic strategy using Janus kinase inhibitors like tofacitinib to reduce SARS-CoV-2 risk in susceptible individuals.
Abstract

Keywords:
Autoimmune DiseaseCOVID-19CoronavirusGenetic SusceptibilityInflammatory Bowel DiseaseSARS-CoV-2Tofacitinib

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