Complement Anaphylatoxins and Inflammatory Cytokines as Prognostic Markers for COVID-19 Severity and In-Hospital Mortality

Authors: Bandar Alosaimi1,2Ayman Mubarak3, Maaweya E. Hamed3Abdullah Z. Almutairi4Ahmed A. Alrashed5, Abdullah AlJuryyan6, Mushira Enani7,Faris Q. Alenzi8 and Wael Alturaiki9*

COVID-19 severity due to innate immunity dysregulation accounts for prolonged hospitalization, critical complications, and mortality. Severe SARS-CoV-2 infections involve the complement pathway activation for cytokine storm development. Nevertheless, the role of complement in COVID-19 immunopathology, complement‐modulating treatment strategies against COVID-19, and the complement and SARS‐CoV‐2 interaction with clinical disease outcomes remain elusive. This study investigated the potential changes in complement signaling, and the associated inflammatory mediators, in mild-to-critical COVID-19 patients and their clinical outcomes. A total of 53 patients infected with SARS-CoV-2 were enrolled in the study (26 critical and 27 mild cases), and additional 18 healthy control patients were also included. Complement proteins and inflammatory cytokines and chemokines were measured in the sera of patients with COVID-19 as well as healthy controls by specific enzyme-linked immunosorbent assay. C3a, C5a, and factor P (properdin), as well as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IgM antibody levels, were higher in critical COVID-19 patients compared to mild COVID-19 patients. Additionally, compared to the mild COVID-19 patients, factor I and C4-BP levels were significantly decreased in the critical COVID-19 patients. Meanwhile, RANTES levels were significantly higher in the mild patients compared to critical patients. Furthermore, the critical COVID-19 intra-group analysis showed significantly higher C5a, C3a, and factor P levels in the critical COVID-19 non-survival group than in the survival group. Additionally, IL-1β, IL-6, and IL-8 were significantly upregulated in the critical COVID-19 non-survival group compared to the survival group. Finally, C5a, C3a, factor P, and serum IL-1β, IL-6, and IL-8 levels positively correlated with critical COVID-19 in-hospital deaths. These findings highlight the potential prognostic utility of the complement system for predicting COVID-19 severity and mortality while suggesting that complement anaphylatoxins and inflammatory cytokines are potential treatment targets against COVID-19.

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

Authors: Anuja Java,1 Anthony J. Apicelli,2 M. Kathryn Liszewski,3 Ariella Coler-Reilly,3 John P. Atkinson,3 Alfred H.J. Kim,3 and Hrishikesh S. Kulkarni4

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.

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Complement control for COVID-19

Authors: Markus Bosmann1,2,3,4,*

The complement system is an integral part of innate immune defense. It consists of about 50 proteins in plasma, on cell surfaces, and inside host cells. The traditional view is that complement proteins guard the local extracellular spaces and systemic bloodstream against invading pathogens. Loss-of-function mutations resulting in terminal complement pathway deficiencies are associated with a 10,000-fold higher risk for life-threatening meningococcal infections in humans. Surprisingly, the complement system is redundant for defense against most pathogens except encapsulated bacteria. Recent concepts embrace the view that complement factors mediate functions inside cells either directly or through surface receptors. Complement activity fine-tunes homeostasis, metabolism, and biogenesis. On the other hand, uncontrolled complement activation causes disease and can even worsen the outcome of infections. Toxic complement effectors mediate tissue destruction and organ injury during inflammatory diseases. Acute respiratory distress syndrome (ARDS) and sepsis are frequent and severe complications of acute infections and notorious for excessive complement consumption. The three pathways of complement activation are designed for immune sensing of nonself surfaces and foreign antigens. The mannose-binding lectin (MBL)/ficolin pathway starts with soluble pathogen pattern recognition receptors as sensors for foreign carbohydrate motifs (Fig. 1). The alternative pathway is fueled by a spontaneous “smoldering” hydrolysis of C3 targeting all surfaces, unless these surfaces present complement inhibitory proteins (CD46, CD55, and CD59) as a protective self-signal. This C3 “tick-over” is sustained by the high concentrations of C3 in plasma (1 to 2 g/liter), the highest level of all complement factors. The classical pathway is initiated by antigen-antibody complexes that are recognized by the multimeric C1 complex. As a safeguard, IgG antibodies bound in clusters or pentameric IgM are required to surpass the activation threshold. All complement pathways converge on C3 convertase complexes leading to C3 cleavage into the larger C3b and the smaller anaphylactic C3a peptides. C3b is essential for the formation of C5 convertase for cleavage of C5 into C5b and the anaphylatoxin C5a. C5b is the starting point of the pore-forming membrane attack complex (MAC) consisting of C5b-C9 with a channel diameter of ~100 Å. The C3/C5 hub represents a gigantic amplification loop. The alternative C3bBb convertase (half-life of ~3 min) cleaves additional C3, resulting in more C3bBb and so on and so forth. This enzymatic chain reaction can deposit millions of C3b molecules on target surfaces in a few seconds. It is no surprise that such explosive events need to be tightly regulated to maintain the delicate balance of effective and justified pathogen attack, while avoiding damage of innocent bystander cells.

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