What’s the verdict on complement in COVID-19?

Complement factors have been proposed to play a role in the pathogenesis of severe SARS-CoV-2 infection. However, complement factors may also contribute to innate and adaptive protective immunity. The roles of complement in COVID-19 need further investigation.

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By Liriye Kurtovic and James G. Beeson

SARS-CoV-2 infection can lead to mild respiratory illness and in some patients, acute respiratory distress syndrome (ARDS), often associated with increased inflammation. One inflammatory mediator that has been in the spotlight recently is the complement system. Complement activity has been reportedly elevated in COVID-19 patients and therefore associated with disease pathology. However, in contrast to this role, complement is known to contribute to immunity against many viral and other pathogens and may also play a protective role against SARS-CoV-2, which is currently unknown. Before ruling that complement is guilty of causing disease, we sought out to review the evidence of complement activation during COVID-19.

Complement is central to the immune system, acting as an innate and adaptive response to infection. We reviewed available clinical studies and found that while serum concentrations of activate complement proteins were elevated in COVID-19 patients, the significance of this was often not clear as levels were often within the normal healthy range. Furthermore, complement activity was considerably lower than observed in other inflammatory syndromes, such as bacterial sepsis. Complement has been shown to enhance antibody-mediated virus neutralization (E.g. West Nile virus), and lead to lysis of the virus (E.g. Zika virus) and virus-infected cells (E.g. influenza virus). Disappointingly, there has been little investigation into the potential role of antibody-complement interactions against SARS-CoV-2. This may be due to the assumption that complement activation is hyper-inflammatory and contributes to disease pathology, but the evidence to support this is limited. On this note, most neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) in development are human IgG1, which has the structural properties to activate complement. Yet, there is no evidence of these mAbs excessively activating complement in clinical trials. We can therefore speculate that antibody-complement interactions are not hyper-inflammatory, although, this needs to be formally evaluated.

Figure: Potential Mechanisms of Innate and Adaptive Complement Activation against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Innate complement activation occurs rapidly against target pathogens via the mannose-binding lectin (not shown) or alternative pathway, the latter initiated by spontaneous C3 activation. Potential mechanisms of innate complement activation against SARS-CoV-2 might include: (i) deposition of C3b that can interact with C3b receptors (CR1, CR3, and CRIg) on phagocytes for clearance and degradation of the virus; and (ii) deposition of C5b and formation of the membrane attack complex (MAC) that creates a pore in the membrane leading to lysis of the virus. Adaptive complement activation is dependent on the acquisition of antigen-specific antibodies, which takes time to develop. Potential mechanisms of adaptive complement activation against SARS-CoV-2 might include: (i) C1q binding to antigen-specific antibody that can significantly enhance antibody-mediated neutralization of the virus, possibly due to a larger antibody–C1q complex more effectively blocking receptor–ligand interactions, or via C1q stabilization or enhancement in the binding of low affinity antibodies, or because C1q might reduce the antibody threshold required for neutralization; (ii) deposition of C3b and phagocytosis; and (iii) C5b deposition, MAC formation and lysis. Figure created using BioRender. From Trends Immunol 42:94-103

There has been interest in the use of complement inhibitors to treat COVID-19. Thus far, only few case reports or case series have been published, which report both positive and negative clinical outcomes for patients receiving complement inhibitors in addition to other therapies. In the one controlled trial performed, complement inhibitor treatment did not significantly improve the primary outcome of respiratory function.

Altogether, complement activity may be elevated in COVID-19 patients and control contribute to disease pathology in some individuals. However, more evidence is needed to support this conclusion. There is currently little known on the potential protective roles of complement, and limited evidence that complement inhibitor therapies have a significant benefit to COVID-19 patients. Until further evidence is available, we rule complement as “not guilty”. Furthermore, complement may have protective roles that need to be investigated.

See the full article here:  https://www.cell.com/trends/immunology/fulltext/S1471-4906(20)30283-0

Table summarizing studies of serum complement concentrations in COVID-19 patients versus controls

https://www.cell.com/action/showFullTableHTML?isHtml=true&tableId=t0005&pii=S1471-4906%2820%2930283-0

References

Kurtovic, L. and Beeson, J.G. (2020) Complement factors in COVID-19 therapeutics and vaccines. Trends in Immunology. 42 (2), 94-103.

Mehlhop, E. et al. (2009) Complement protein C1q reduces the stoichiometric threshold for antibody-mediated neutralization of West Nile virus. Cell Host & Microbe 6 (4), 381-391.

Du, H. et al. (2020) Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status. Allergy, 2020;00:1–23.

Vlaar, A.P. et al. (2020) Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. The Lancet Rheumatology 2 (12), E764-E773.

James Beeson

Deputy Director and Research Fellow, Burnet Institute

James is a public health physician and PhD graduate who has worked on the pathogenesis and immunology of malaria for many years through clinical and population studies and clinical trials. The major focus of his research is aimed at understanding the targets and mechanisms of protective immunity to malaria in humans, how protective immunity is acquired and maintained, and using this knowledge to advance malaria vaccine development and evaluation.

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