Severely ill COVID-19 Patients Benefit from the Use of Complement Inhibitors

Researchers have identified several antibodies to the nucleocapsid protein from a convalescent COVID-19 patient. Tests found some can inhibit complement hyperactivation and could potentially lead to new therapeutics. Studies have suggested that a hyperactive complement system, a part of the immune system that increases the ability of antibodies to fight infections, predisposes patients to adverse COVID-19 outcomes. Hyperactivation of the complement system, which usually helps with immunity, can lead to tissue injury.

The team collected samples from six patients in China about 7–25 days after symptom onset. From the sample of one patient, who completely recovered within nine days of symptom onset, they found 32 monoclonal antibodies that reacted to the nucleocapsid protein, which included 20 antibodies from plasma cells and 12 from memory B cells. In contrast, they found only eight monoclonal antibodies to the spike protein.

The binding of the antibody causes several conformational changes in the N-terminal domain, leading to the binding pocket becoming bigger and partial unfolding of the basic palm region. The researchers also developed a method to study levels of complement activation in the presence of the SARS-CoV-2 nucleocapsid protein. They found that the nucleocapsid protein induces hyperactivation of MASP-2 proteases, enzymes used in complement activation. Addition of a nucleocapsid antibody identified before reduced the rate of reaction of the complement hyperactivation.

This inhibition was also seen with three other nucleocapsid protein antibodies identified. However, the exact interaction of the virus with protease is still unknown. There is growing evidence that severely ill COVID-19 patients benefit from the use of complement inhibitors, with several clinical trials underway.

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https://www.nature.com/articles/s41467-021-23036-9

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