Soluble ACE2 correlates with severe COVID-19 and can impair antibody responses

Mikhail Lebedin; Christoph Ratswohl; Amar Garg; Marta Schips; Clara Vázquez García; Lisa Spatt; Charlotte Thibeault; Benedikt Obermayer; January Weiner; Ilais Moreno Velásquez; Cathrin Gerhard; Paula Stubbemann; Leif-Gunnar Hanitsch; Tobias Pischon; Martin Witzenrath; Leif Erik Sander; Florian Kurth; Michael Meyer-Hermann; Kathrin de la Rosa

doi:10.1016/j.isci.2024.109330

Soluble ACE2 correlates with severe COVID-19 and can impair antibody responses

iScience. 2024 Feb 24;27(3):109330. doi: 10.1016/j.isci.2024.109330. eCollection 2024 Mar 15.

Authors

Mikhail Lebedin^{1

2}, Christoph Ratswohl^{1

3}, Amar Garg⁴, Marta Schips⁴, Clara Vázquez García^{1

2}, Lisa Spatt¹, Charlotte Thibeault⁵, Benedikt Obermayer⁶, January Weiner⁶, Ilais Moreno Velásquez⁷, Cathrin Gerhard¹, Paula Stubbemann⁵, Leif-Gunnar Hanitsch⁵, Tobias Pischon^{2

7

8}, Martin Witzenrath^{5

9

10}, Leif Erik Sander^{5

9

11}, Florian Kurth^{5

9}, Michael Meyer-Hermann^{4

12}, Kathrin de la Rosa^{1

2

11}

Affiliations

¹ Max-Delbück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
² Charité-Universitätsmedizin Berlin, Berlin, Germany.
³ Free University of Berlin, Department of Biology, Chemistry and Pharmacy, 14195 Berlin, Berlin, Germany.
⁴ Helmholtz Centre for Infection Research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.
⁵ Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
⁶ Core Unit Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
⁷ Molecular Epidemiology Research Group, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
⁸ Biobank Technology Platform, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany.
⁹ German Center for Lung Research (DZL), 35392 Gießen, Germany.
¹⁰ CAPNETZ STIFTUNG, 30625 Hannover, Germany.
¹¹ Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
¹² Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany.

Abstract

Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-receptor-binding motif (RBM). We tested 717 longitudinal samples from 295 COVID-19 patients and showed a 2- to 10-fold increase of enzymatically active sACE2 (a-sACE2), with up to 1 μg/mL total sACE2 in moderate and severe patients. Fifty percent of COVID-19 sera inhibited ACE2 activity, in contrast to 1.3% of healthy donors and 4% of non-COVID-19 pneumonia patients. A mild inverse correlation of a-sACE2 with RBM-directed serum antibodies was observed. In silico, we show that sACE2 concentrations measured in COVID-19 sera can disrupt germinal center formation and inhibit timely production of high-affinity antibodies. We suggest that sACE2 is a biomarker for COVID-19 and that soluble receptors may contribute to immune suppression informing vaccine design.

Keywords: Human specimen; Immune response; In silico biology; Properties of biomolecules.