Background/Purpose: The ectopeptidase CD13, which is highly expressed on stromal and myeloid cells in joints, lung and other tissues, is a known receptor for many coronaviruses. Its soluble form (sCD13) is a powerful pro-inflammatory mediator with strong chemotactic, angiogenic and arthritogenic properties. Neutrophil extracellular traps (NETs) are known to trigger formation of thrombi in antiphospholipid syndrome (APS), and likely also in other inflammatory and rheumatologic conditions. Recently NET-associated markers have been shown to correlate with disease severity in COVID-19 patients. Moreover, sera from COVID-19 patients trigger healthy neutrophils to undergo NETosis. We hypothesized that CD13 is also a receptor for SARS-CoV-2, and that both the cell membrane-anchored and soluble forms of CD13 trigger aggressive inflammatory responses in SARS-CoV-2 infection, including NETosis.

Methods: Serum samples from healthy volunteers (n=53) and hospitalized COVID-19 patients (n=172) were used in this study. The levels of sCD13, citrullinated histone H3 (Cit-H3), and MPO-DNA complexes were measured by ELISA. NETosis was measured by SYTOX Green and NET-associated elastase activity. GraphPad Prism v8 was used for statistical analysis. The Mann-Whitney test or Kruskal-Wallis test was used to compare groups. Correlation was tested by Spearman’s correlation coefficient. Statistical significance was defined as p< 0.05.

Results: Significant elevation of sCD13 was observed in COVID-19 patients as compared with healthy subjects (960 ± 81.2 vs. 94.7 ± 37.6 ng/ml, mean ± SEM, p< 0.0001), with the highest levels observed in patients who required mechanical ventilation. sCD13 levels were two-fold higher in African American compared to Caucasian patients (p=0.02). In addition, sCD13 positively correlated with inflammation-indicative markers, including ferritin (r=0.252, p=0.002) and lactate dehydrogenase (r=0.374, p< 0.0001), as well as NETosis-related markers, such as Cit-H3 (r=0.243, p=0.001) and MPO-DNA (r=0.242, p=0.001). Both sCD13 and anti-CD13 monoclonal antibodies induced robust NETosis in control neutrophils in vitro.

Conclusion: Although not yet identified as a cell surface receptor for cell entry of the novel coronavirus SARS-CoV-2, CD13—which is much more widely expressed than ACE2—could play several unique roles in viral pathogenesis. These data identify CD13 and a cell surface receptor for sCD13 as potential triggers for COVID-19-associated NETosis, vascular stress and thromboembolic complications. The powerful pro-inflammatory effects of sCD13 may account for an important component of the unusual hyperinflammatory complications of this viral infection. Receptors for sCD13, one of which we have recently identified as the bradykinin 1 receptor (B1R) could become therapeutic targets in patients with severe COVID-19.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-cd13-as-a-potential-cause-for-sars-cov-2-triggered-hyperinflammation-and-thrombosis/