The complement system in COVID-19: friend and foe?

Abstract

Interplay between SARS-CoV-2 and the complement system Antiviral strategies. The complement system traces its origins to more than a billion years ago when primitive proteins evolved to protect cells from pathogens and to engage in intracellular metabolic processes (18, 19) (Figure 1A). The contemporary complement system lies at the interface between innate and adaptive immunity (20). It efficiently recognizes and eliminates viral pathogens via several mechanisms: opsonizing viruses and virus-infected cells (including lysing them), inducing an antiviral immunoinflammatory state, boosting virus-specific immune responses, and directly neutralizing cell-free viruses (21) (reviewed in ref. 22). Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19-related morbidity and mortality have been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized. Here, we summarize current knowledge about the interaction of coronaviruses with the complement system. We posit that (a) coronaviruses activate multiple complement pathways; (b) severe COVID-19 clinical features often resemble complementopathies; (c) the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19; (d) a subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation; and (e) these observations create a basis for clinical trials of complement inhibitors in life-threatening illness.

Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19

“…Therefore, it is interesting to note that C3 consumption is a general sign of C3 convertase activity, which would be a prerequisite for the downstream generation of membrane attack components (Leslie and Nielsen, 2004). Along those lines, complement activation has been implicated in the pathogenesis of COVID-19-related end-organ damage, including acute lung injury (Java et al, 2020;Magro et al, 2020), with potential therapeutic implications (Kulasekararaj et al, 2020;Smith et al, 2020). Finally, MT DAMPs, unlike other inflammatory markers linked to poor outcomes of COVID-19 afflicted patients, have been reported to directly cause acute pulmonary dysfunction and tissue damage (Lee et al, 2017).…”

A Review on the Neurological Manifestations of COVID-19 Infection: a Mechanistic View

“…Furthermore, local elevated production of cytokines in the cerebral tissue can induce inflammation [73] and lead to neurologic features observed in COVID-19 patients [74]. It should be also mentioned that viral components are capable to interact with various molecules, such as pattern recognition receptors (e.g., Toll-like receptors), NF-κB, complement cascades, certain transcription factors, and cell apoptosis mediators [62,75]. Following the entrance of the virus into the CNS, miscellaneous signaling pathways inside or between cells could be modified, and cerebral neurotransmitters and local hormones may be dysregulated.…”

Development and validation of a machine learning-based prediction model for near-term in-hospital mortality among patients with COVID-19

“…32 33 Key markers of inflammation-C reactive protein and complement C4 together with the markers of coagulability-D-dimer, platelet count and activated partial thromboplastin time being predictive in our model, is consistent with the suggestion of severe COVID-19 being coagulopathy with severe immuneinflammatory state. 34 Predictive value of ECG variables, such as the axis of T wave, PR interval, indicates importance of cardiac complications in COVID-19 in relation to patient outcome. 35 36 Contradictory to the expectation, the N-terminal pro-B-type natriuretic peptide (NT-proBNP), a predictor of mortality in COVID-19, 37 ranked low in our model.…”