Complement dysregulation is associated with severe COVID-19 illness
Jia Yu1, Gloria F Gerber1, Hang Chen1
1Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD.
Insights
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) triggers complement system activation, leading to cell damage in COVID-19 patients. This complement dysregulation is linked to disease severity and may be a therapeutic target.
Area of Science:
- Immunology
- Virology
- Pathogenesis of Infectious Diseases
Background:
- Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can lead to severe complications including thrombosis and organ failure.
- Complement system activation has been implicated in the pathogenesis of various diseases, including COVID-19.
- Previous research indicated SARS-CoV-2 spike protein's role in activating the alternative pathway of complement (APC).
Purpose of the Study:
- To investigate the role of complement activation in COVID-19 pathogenesis.
- To assess the correlation between complement dysregulation and COVID-19 disease severity.
- To explore the mechanism by which SARS-CoV-2 spike protein affects complement regulation.
Main Methods:
- Functional assays (modified Ham test) were used to measure complement-mediated cell death induced by serum from 58 COVID-19 patients.
- Membrane attack complex (C5b-9) deposition was assessed.
- Inhibition of complement components (C5, Factor D) and measurement of Factor Bb levels were performed.
- Interaction between SARS-CoV-2 spike protein and complement factor H was analyzed.
Main Results:
- Serum from COVID-19 patients induced complement-mediated cell death and increased C5b-9 deposition.
- A positive modified Ham assay was observed in 41.2% of intubated patients versus 6.3% of minimally oxygen-dependent patients.
- Inhibition of C5 and Factor D reduced complement amplification; increased Factor Bb levels correlated with disease severity.
- SARS-CoV-2 spike protein was shown to inhibit complement factor H binding to heparin.
Conclusions:
- Complement dysregulation, particularly APC activation, contributes to COVID-19 pathogenesis.
- Complement activation is associated with COVID-19 disease severity.
- Targeting the complement system may offer a therapeutic strategy for COVID-19.
Abstract:
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other complement- mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of COVID-19 illness. We previously found that the SARS-CoV-2 spike protein activates the alternative pathway of complement (APC) in vitro through interfering with the function of complement factor H, a key negative regulator of APC. Here, we demonstrated that serum from 58 COVID-19 patients (32 patients with minimal oxygen requirement, 7 on high flow oxygen, 17 requiring mechanical ventilation and 2 deaths) can induce complementmediated cell death in a functional assay (the modified Ham test) and increase membrane attack complex (C5b-9) deposition on the cell surface. A positive modified Ham assay (>20% cell-killing) was present in 41.2% COVID-19 patients requiring intubation (n=7/17) and only 6.3% in COVID-19 patients requiring minimal oxygen support (n=2/32). C5 and factor D inhibition effectively mitigated the complement amplification induced by COVID-19 patient serum. Increased serum factor Bb level was associated with disease severity in COVID-19 patients, suggesting that APC dysregulation plays an important role. Moreover, SARS-CoV-2 spike proteins directly block complement factor H from binding to heparin, which may lead to complement dysregulation on the cell surface. Taken together, our data suggest that complement dysregulation contributes to the pathogenesis of COVID-19 and may be a marker of disease severity.
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