Emerging role of complement in COVID-19 and other respiratory virus diseases

Abstract

The complement system, a key component of innate immunity, provides the first line of defense against bacterial infection; however, the COVID-19 pandemic has revealed that it may also engender severe complications in the context of viral respiratory disease. Here, we review the mechanisms of complement activation and regulation and explore their roles in both protecting against infection and exacerbating disease. We discuss emerging evidence related to complement-targeted therapeutics in COVID-19 and compare the role of the complement in other respiratory viral diseases like influenza and respiratory syncytial virus. We review recent mechanistic studies and animal models that can be used for further investigation. Novel knockout studies are proposed to better understand the nuances of the activation of the complement system in respiratory viral diseases.

Keywords: Animal models; Complement; Influenza; MAC; Respiratory syncytial virus; SARS-CoV-2.

Figure 1.

Complement (C) activation, regulation, and C-targeted therapeutics: Complement is activated by classical. Lectin and alternative pathways, which leads to forming the complement activation bi-products such as C3a, C5a, and membrane attack complex (MAC). Complement activation is restricted by an array of host complement regulators. The therapeutics listed include complement-targeted therapy used in clinical trials for the treatment of COVID-19. FI Factor I, FH, Factor H, FP Properdin, C1INH, C1 esterase inhibitor, LPS lipopolysaccharide, MLB Mannose-Binding Lectin, FCN Ficolin, MASP Mannose-Associated Serine Protease. Adapted from: Lim et al. Blood Rev. (2023). Generated in Microsoft Powerpoint

Fig. 2

SARS-CoV-2 mediates complement activation and tissue damage and causes the relapse of complement dysregulation-related diseses: SARS-CoV-2 cellular invasion is mediated by ACE2 receptor binding. Beyond viral mediated cell lysis, SARS-CoV-2 can cause damage to tissues in the lungs, endothelia, kidneys, and other organs via the direct activation (and the inhibition of regulation) of the complement system. SARS-CoV-2 can also mediate the relapse of complement dysregulation-mediated diseases such as atypical hemolytic uremic syndrome (aHUS), Complement-mediated thrombotic microangiopathy (TMA) and paroxysmal Nocturnal Hemoglobinuria (PNH) (highlighted in red). BALF bronchiolar Lavage Fluid, ARDS Acute Respiratory Distress Syndrome. S Protein Spike Protein, MAC Membrane Attack Complex, N Protein Nucleocapsid Protein. Images used were imported from online sources under creative commons use licenses or generated in Microsoft Powerpoint.