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Distinct soluble immune checkpoint profiles characterize COVID-19 severity, mortality and SARS-CoV-2 variant
Tudorita Gabriela Paranga1,2, Mariana Pavel-Tanasa3,4, Daniela Constantinescu3,4
1Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania.
Introduction:
Over the past four years, the COVID-19 pandemic has posed serious global health challenges. The severe form of disease and death resulted from the failure of immune regulatory mechanisms, closely highlighted by the dual proinflammatory cytokine and soluble immune checkpoint (sICP) storm. Identifying the individual factors impacting on disease severity, evolution and outcome, as well as any additional interconnections, have become of high scientific interest.
Methods:
In this study, we evaluated a novel panel composed of ten sICPs for the predictive values of COVID-19 disease severity, mortality and Delta vs. Omicron variant infections in relation to hyperinflammatory biomarkers. The serum levels of sICPs from confirmed SARS-CoV-2 infected patients at hospital admission were determined by Luminex, and artificial neural network analysis was applied for defining the distinct patterns of molecular associations with each form of disease: mild, moderate, and severe.
Results:
Notably, distinct sICP profiles characterized various stages of disease and Delta infections: while sCD40 played a central role in all defined diagrams, the differences emerged from the distribution levels of four molecules recently found and relatively less investigated (sCD30, s4-1BB, sTIM-1, sB7-H3), and their associations with various hematological and biochemical inflammatory biomarkers. The artificial neural network analysis revealed the prominent role of serum sTIM-1 and Galectin-9 levels at hospital admission in discriminating between survivors and non-survivors, as well as the role of specific anti-interleukin therapy (Tocilizumab, Anakinra) in improving survival for patients with initially high sTIM-1 levels. Furthermore, strong associations between sCD40 and Galectin-9 with suPAR defined the Omicron variant infections, while the positive match of sCD40 with sTREM-1 serum levels characterized the Delta-infected patients.
Conclusions:
Of importance, this study provides a comprehensive analysis of circulatory immune factors governing the COVID-19 pathology, and identifies key roles of sCD40, sTIM-1, and Galectin-9 in predicting mortality.
Insights
This study identified key soluble immune checkpoint (sICP) profiles that predict COVID-19 severity and mortality. Specific sICPs like sTIM-1 and Galectin-9 are crucial for determining patient outcomes and guiding therapy.
Area of Science:
- Immunology
- Virology
- Computational Biology
Background:
- COVID-19 pandemic caused global health challenges due to immune dysregulation.
- Severe disease and mortality linked to cytokine storm and soluble immune checkpoints (sICPs).
- Understanding factors influencing COVID-19 severity and outcomes is critical.
Purpose of the Study:
- Evaluate a novel panel of ten sICPs for predicting COVID-19 severity, mortality, and variant infections (Delta vs. Omicron).
- Investigate associations between sICPs and hyperinflammatory biomarkers.
- Define molecular patterns related to disease severity using artificial neural network analysis.
Main Methods:
- Serum sICP levels measured in hospitalized SARS-CoV-2 patients using Luminex.
- Artificial neural network analysis applied to identify patterns of molecular associations.
- Correlated sICP profiles with hematological and biochemical inflammatory markers.
Main Results:
- Distinct sICP profiles identified for different disease stages and Delta variant infections, with sCD40 playing a central role.
- Serum sTIM-1 and Galectin-9 levels at admission predicted survivor status.
- Specific anti-interleukin therapies improved survival in patients with high sTIM-1.
- Omicron variant infections associated with sCD40/Galectin-9/suPAR; Delta variant infections with sCD40/sTREM-1.
Conclusions:
- Circulatory immune factors significantly influence COVID-19 pathology.
- sCD40, sTIM-1, and Galectin-9 are key predictors of COVID-19 mortality.
- sICP profiling offers insights into variant-specific disease characteristics and therapeutic targets.
