Conclusion and future perspective
In summary, the available data strongly support a model in which complement activation in the lung and in other organs is a critical host mediator of SARS-CoV-2-induced development of atypical ARDS and TMA. We would like to propose a model in which strong complement activation by the LP and/or the CP occurs in patients suffering from atypical ARDS/TMA resulting in massive generation of C5a. Polymorphisms in exon 1 and/or the promoter region of MBL or in complement regulators may define the extent of complement activation, in particular in African Americans. Alternatively, and not mutually exclusive, the extent of virus-specific neutralizing IgG Abs generated after the first week of infection may determine the magnitude of complement activation. Importantly, C5a controls the threshold of IgG Fc receptor expression as an important mechanism of IgG-mediated innate immune cell activation (Karsten & Kohl, 2012). Complement activation occurs primarily in the lower airways but will result in the release of C5a into the circulation. Such C5a recruits and activates proinflammatory immune cells as a key mechanism that drives the “cytokine and chemokine storm” associated with fatal lung injury and TMA development (Figure 2). Thus, targeting C5, C5a or its primary receptor, C5aR1, should be considered to alleviate the proinflammatory effects, reduce lung pathology and increase the survival of COVID-19 patients.