Complement System

The complement system is part of the innate immune system and plays an important role in the host defense, inflammation, tissue regeneration and other physiological processes. Complement activation results in opsonization of pathogens and their removal by phagocytes. It also causes chemotactic attraction of phagocytes and macrophages. Furthermore, the complement system forms the terminal attack complex (MAC), a membrane channel causing osmotic lysis of the respective pathogen. While complement is not adaptable it does complement the adaptive immune system and it is also involved in B and T cell response regulation.

Activation of complement unfolds along three different complement activation pathways depending on the nature of the pathogen: the classical pathway, the lectin pathway, and the alternative pathway. All three converge into the common terminal pathway that leads to the formation of the MAC. In addition, anaphylatoxins C3a and C5a elicit a plethora of physiological responses that range from chemoattraction to apoptosis. The complement system consists of more than 30 proteins that are either present as soluble proteins in the blood or as membrane-associated proteins. Most exist as inactive zymogens that are then sequentially cleaved and activated. The central component in all three pathways is component C3, the most abundant complement protein found in the blood. Its activation induces the formation of the activation products C3a, C3b, and C5a and ultimately the MAC.

In addition to these three established pathways, it has been shown that factors such as kallikrein, plasmin, thrombin, and factor XIIa activate the complement system independently of the C3 protein.

In COVID-19, the SARS-CoV-2 nucleocapsid protein protein triggers activation of the lectin pathway of the complement system through interaction with mannose binding lectin (MBL)-associated serine protease (MASP)2. Released soluble N protein dimers interact with MASP-2, further accelerating MASP-2 activation and activation of the complements system. The positive feedback through cell lysis and release of N-protein leads to elevation of pro-inflammatory cytokines, characterized as cytokine storm.

N-protein neutralization is a promising avenue for a COVID-19 therapy, as well as the targeted inhibition of MASP-2. Suppressive effects could also be observed with anti-C5a antibody treatment.

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