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Live Imaging and Quantification of Viral Infection in K18 hACE2 Transgenic Mice Using Reporter-Expressing Recombinant SARS-CoV-2
Published on: November 5, 2021
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The endogenous cellular protease inhibitor SPINT2 controls SARS-CoV-2 viral infection and is associated to disease
Carlos Ramirez Alvarez1, Carmon Kee2,3, Ashwini Kumar Sharma1
1Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg, Germany.
Plos Pathogens
|June 28, 2021
Summary
The serine protease TMPRSS2 aids SARS-CoV-2 entry. SPINT2 inhibits TMPRSS2, and its reduced expression in COVID-19 patients correlates with increased viral load, suggesting a therapeutic target.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry into host cells is facilitated by the serine protease TMPRSS2.
- The regulation of TMPRSS2 activity is crucial for understanding viral pathogenesis, yet remains largely uncharacterized.
- SPINT2, a Kunitz-type serine protease inhibitor, is known to inhibit TMPRSS2 activity.
Purpose of the Study:
- To investigate the co-regulation between SPINT2 and TMPRSS2.
- To determine the role of SPINT2 in SARS-CoV-2 infection and its potential link to COVID-19 comorbidities.
Main Methods:
- Analysis of SPINT2/TMPRSS2 expression balance across various tissues.
- Correlation analysis of SPINT2 expression with SARS-CoV-2 replication in Calu-3 and Caco-2 cell lines.
- SPINT2 knockdown and overexpression experiments in Calu-3 cells to assess viral load.
- Evaluation of SPINT2 expression in datasets from comorbid diseases (cancer, diabetes) using bulk and single-cell RNA sequencing.
Main Results:
- A tightly regulated expression balance between SPINT2 and TMPRSS2 was observed across tissues.
- SPINT2 expression negatively correlated with SARS-CoV-2 in lung and intestinal cell lines.
- SPINT2 was down-regulated in secretory cells of COVID-19 patients.
- SPINT2 knockdown increased viral load, while overexpression reduced it in Calu-3 cells.
- SPINT2 down-regulation was noted in colon, kidney, and liver tumors, and in pancreatic islet cells from Type 2 diabetes patients.
Conclusions:
- SPINT2 acts as a crucial regulator of TMPRSS2 activity, impacting SARS-CoV-2 entry and replication.
- Down-regulation of SPINT2 may contribute to increased viral load in COVID-19 patients.
- Altered SPINT2 expression in comorbid conditions suggests a potential link to COVID-19 severity and pathogenesis in patients with chronic diseases.
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