Can there be calm during a cytokine storm? Immune checkpoint pathways affecting the severity of COVID-19 disease

Matyas Meggyes; David U Nagy; Ildiko Toth; Timoteus Feik; Agnes Peterfalvi; Beata Polgar; David Sipos; Agnes Kemeny; Laszlo Szereday

doi:10.3389/fmicb.2024.1508423

Can there be calm during a cytokine storm? Immune checkpoint pathways affecting the severity of COVID-19 disease

Front Microbiol. 2024 Dec 23:15:1508423. doi: 10.3389/fmicb.2024.1508423. eCollection 2024.

Authors

Matyas Meggyes^{1

2}, David U Nagy³, Ildiko Toth⁴, Timoteus Feik¹, Agnes Peterfalvi⁵, Beata Polgar¹, David Sipos⁶, Agnes Kemeny^{7

8}, Laszlo Szereday^{1

2}

Affiliations

¹ Department of Medical Microbiology and Immunology, Medical School, University of Pecs, Pecs, Hungary.
² Janos Szentagothai Research Centre, Pecs, Hungary.
³ Institute of Geobotany/Plant Ecology, Martin-Luther-University, Halle, Germany.
⁴ Department of Anesthesiology and Intensive Therapy, Medical School, University of Pecs, Pecs, Hungary.
⁵ Department of Laboratory Medicine, Medical School, University of Pecs, Pecs, Hungary.
⁶ Division of Infectious Diseases, 1st Department of Medicine, Medical School, University of Pecs, Pecs, Hungary.
⁷ Department of Pharmacology and Pharmacotherapy, Medical School, University of Pecs, Pecs, Hungary.
⁸ Department of Medical Biology and Central Electron Microscopic Laboratory, Medical School, University of Pecs, Pecs, Hungary.

Abstract

Introduction: The COVID-19 pandemic has become a global health crisis, eliciting varying severity in infected individuals. This study aimed to explore the immune profiles between moderate and severe COVID-19 patients experiencing a cytokine storm and their association with mortality. This study highlights the role of PD-1/PD-L1 and the TIGIT/CD226/CD155/CD112 pathways in COVID-19 patients.

Methods: We performed a study using flow cytometry to compare the phenotypic and functional characteristics of peripheral blood mononuclear cells in patients with moderate or severe disease and healthy individuals. Soluble immune checkpoint molecule and ligand levels were measured by Luminex.

Results: Severe patients show reduced CD8+ T cell frequency, hyperactivation of CD8+ T, NK and NKT cells with concurrent upregulation of immune checkpoint ligands in monocytes. TIGIT expression by CD8+ T and NK cells and PD-1 by NKT cells suggest a spectrum of immune dysfunction, encompassing both hyperactivation and features of exhaustion. This dual phenomenon likely contributes to the impaired viral clearance and the exacerbation of inflammation characteristic of severe disease. Additionally, the study suggests that increased activation and cytotoxicity of NK cells may be associated with fatal outcomes in severe COVID-19 infection.

Conclusion: These findings shed light on the intricate immune response regulation in COVID-19, emphasizing the importance of immune checkpoint pathways and activation signatures in disease severity. A novel aspect of this study is that it includes only COVID-19 patients experiencing cytokine storms, allowing for a focused analysis of immune dysregulation during this critical phase of the disease.

Keywords: COVID-19; SARS-CoV-2; cytokine storm; immune checkpoints; immune dysregulation.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the University of Pecs Medical School Research Grant (PTE-AOK KA 2021–29, KA 2021–38).