Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Proteome profiling in COVID-19 patients reveals CXCL1 as potential therapeutic target
A. A. Derda1, B. Seeliger2, S. Chatterjee3, D. Lu3, T. Welte2, J. Bauersachs1, S. David4, C. Bär3, T. Thum3
1Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover; 2Abteilung Pneumologie, Medizinische Hochschule Hannover, Hannover; 3Institut für Molekulare und Translationale Therapiestrategien, OE-8886, Medizinische Hochschule Hannover, Hannover; 4Institut für Intensivmedizin, UniversitätsSpital Zürich, Zürich, CH;

Introduction

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic that broke out in 2019, and has since already claimed the lives of millions of victims and poses significant socioeconomic problems for society. Although some vaccines are now approved on the market, target structure-based mechanistic treatment strategies of already infected individuals are scarce. Our goal was to employ proteomic analyses in the blood of healthy volunteers, severely-sick COVID-19 patients, and severely-sick influenza patients as a control group for ARDS (Acute Respiratory Distress Syndrome) of another origin to identify new mechanistic insights.

Methods

Proteomic analyses were performed in serum of critically ill COVID-19 patients (n = 10), critically ill influenza patients (n = 10), and healthy volunteers (n = 10). All three groups had comparable age and gender distributions. The two disease groups were also matched based on the duration of ventilation, ICU treatment time, catecholamine dose, use of extracorporeal membrane oxygenation (ECMO), survival, and the Horowitz index. 368 proteins in the blood associated with the cardiovascular system and inflammatory processes were analysed using proximity extension assay-based analyses.

Results

Post-hoc hierarchical clustering and principal component analysis of the proteomic data revealed a clear separation between COVID-19 and controls, but also between COVID-19 and non-COVID-ARDS patients (influenza). Amongst all deregulated proteins, cytokine CXCL1 showed a strong upregulation in COVID-19 compared to both the control and the non-COVID-ARDS (influenza) cohort (p = 0.0312). The results suggest that the cytokine CXCL1 associated with inflammatory processes may play a substantial role in the pathogenesis of severe COVID-19 infection. Next, we differentiated cardiomyocytes from human induced pluripotent stem cells (hiPSC) followed by infection with SARS-CoV-2. RNA sequencing of these cells also revealed a strong induction of CXCL1 compared with control hiPSC cardiomyocytes. To further characterize CXCL1, we are currently performing ELISA-based staining of human cardiac tissues from SARS-CoV-2-infected individuals and comparing them with tissues from healthy and influenza-infected individuals. A potential mechanistic role in human cardiomyocytes is currently investigated through gain-and loss of function studies.

Conclusion

Through extensive proteomic analyses of blood from severely ill COVID-19 patients and RNA sequencing at the cellular level, we identified CXCL1 as a potential therapeutic target for treating severe COVID-19 infection. 

https://dgk.org/kongress_programme/jt2022/aV364.html