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.