Multiple-Organ Complement Deposition on Vascular Endothelium in COVID-19 Patients.

Paolo Macor,Rossana Bussani,Luca De Maso,Francesco Tedesco,Martina Zanon,Nicola Pozzi,Stefano D’Errico,Paolo Durigutto,Pier Luigi Meroni,Alessandro Mangogna

doi:10.3390/biomedicines9081003

Abstract

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to investigate the deposition of complement components in the lungs, kidneys, and liver in patients with COVID-19 patients and to determine the pathway/s of complement activation. We performed immunofluorescence analyses of autopsy specimens of lungs, kidney, and liver from 12 COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG, and spike protein of SARS-CoV-2. Lung deposits of C1q, C4, C3, and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. FB deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on the hepatic artery and portal vein of the liver. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease and the contribution of the complement system to inflammation and tissue damage.

Highlights

IntroductionThe vast majority of individuals infected by the new coronavirus SARS-CoV-2 manifests mild to moderate disease and usually recover within a few weeks
To determine if C was activated by other initiators of the lectin pathway, such as ficolins and collectins, we examined the autopsy specimens for the presence of MASP-2, which is strictly required for the activation of the lectin pathway; but, as for MBL, the staining was negative
We looked into the activation of the alternative pathway by staining the sections for Factor B (FB), which was detectable (Figure 1), and concluded that, in addition to the classical pathway, the alternative pathway must be playing an important role in C activation in these patients

Summary

Introduction

The vast majority of individuals infected by the new coronavirus SARS-CoV-2 manifests mild to moderate disease and usually recover within a few weeks. Some of them, for unknown reasons, experience a severe form of disease and require intensive care treatment [1,2]. The respiratory tract is considered the main target of SARS-CoV-2 that infects epithelial cells in the trachea and bronchi and pneumocytes in the lungs, causing pneumonia, that in more severe cases, progresses to acute respiratory distress syndrome [3]. Other organs may be involved, including the heart, kidneys, and liver [4], due to the wide distribution of the virus receptor ACE-2 [5,6]. Consistent with the multiorgan nature of this complex disease, analysis of a large number of COVID-19 patients has Biomedicines 2021, 9, 1003.

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