The Complement – Behind Enemy Lines

November 16, 2021 0 By Gopakumar

Despite a plethora of scientific literature available on SARS- CoV2, SARS-CoV and MERS-CoV, there are still uncertainties that impede identification of new therapies

Lakshmy Ramakrishnan

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) is the etiologic agent of COVID-19, which has infected more than 239 million individuals and caused over 4.8 million deaths worldwide. The clinical presentation of COVID-19 is considered to be broad, as patients present themselves as either asymptomatic carriers, those with mild to moderate symptoms that do not require hospitalisation, or those with severe COVID-19. A significant portion of those with severe disease progressively worsen and often require ventilatory support from intensive care units (ICUs). Critically ill patients have been observed to develop acute respiratory failure, acute renal failure, circulatory shock, and thrombotic complications. In India, of the 34 million SARS-CoV2 cases, a significant proportion has required ICU-based care, but it is likely that this figure will rise, as the struggle against COVID-19 continues. Despite there being a plethora of scientific literature available on SARS-CoV2, particularly on preprint servers and from studies on SARS-CoV and MERS-CoV, there is still a great deal of uncertainty. In particular, there is a lack of understanding of viral pathophysiology and host immune responses during SARS-CoV2 infection, impeding the identification of new therapies that will ultimately aid in the treatment and management of the disease. 

The current understanding of the development of severe disease is that it is not only a consequence of viral infection but is also due to a dysregulated adaptive immune response, resulting in a cytokine storm phenomenon. Most recently, however, scientists have begun to explore the role of the complement in COVID-19 infections. The complement system forms part of the innate immune system and comprises over 30 proteins organised into 3 pathways – the classical, the lectin and the alternative. These components act to complement the activities of antibodies and phagocytes through opsonization of pathogens, recruitment of neutrophils and monocytes to the site of injury, and enhancement of the adaptive immune response. The 3 pathways converge on the C3 component of the system, triggering the formation of the final component, the membrane attack complex (MAC or C5b-9), leading to cell lysis. Undoubtedly, the complement is a robust defender against pathogens, but it is also well established that uncontrolled complement activation can result in damage to tissues, leading to sepsis and multi-organ failure. This suggests that in clinical settings, in the presence of hyper-inflammation and thrombotic events, it is worthwhile to evaluate the beneficial effects of complement activation with its deleterious ones. 

A major indicator of complement’s role in COVID-19 stemmed from studies in SARS-CoV, where the development of acute respiratory distress syndrome (ARDS) was attributed to complement activation. Mice deficient in C3 were observed to have reduced infiltration of monocytes and neutrophils in the lungs and lung damage was also found to be lessened, compared to the control group. In a recent preprint report, immunohistochemistry (IHC) analysis of lung tissue from patients who had suffered from ARDS, as a result of COVID-19, revealed the presence of complement components, including, mannose-binding lectin (MBL), C3, and C5b-9 in alveolar epithelial cells. Another study reported findings of C5b-9 deposits in the proximal tubular cells of the kidney in COVID-19 patients, suggestive of its contribution to acute kidney injury (AKI). Moreover, a study observed high levels of C3a and C5a in the serum of patients suffering from severe COVID-19 compared to those displaying mild symptoms, indicating the presence of complement components in circulation. An interesting observation made by Margo et al., is the presence of microvascular injury in the skin and lung tissue of COVID-19 patients. These events have brought into consideration a possible cross-talk between two dynamic systems: the complement system and the coagulation pathway. It is speculated that upon SARS-CoV2 infection, complement activation triggers a serine protease, MASP-2, to initiate the coagulation cascade, while anaphylatoxins C3a and C5a stimulate neutrophil extravasation to endothelial cells. The latter triggers the formation of neutrophil extracellular traps (NETs), which can act as a scaffold for further clot formation. The complement system, an important component of the innate immune system, normally interacts with the coagulation pathway to ensure physiological equilibrium. Here, however, an inflammatory feedback loop between the two systems triggers extensive tissue damage and thromboses, ultimately resulting in a destructive response that is detrimental to the host. It is with this consideration that clinicians and scientists have turned to analysing the complement-coagulation interplay as a crucial factor that requires management during SARS-CoV2 infection.

Taking into consideration these challenges, complement-targeted therapies are of considerable interest. Several clinical trials are underway, targeting either specific components of the pathway or the entire pathway. Earlier this year, AMY-101, a C3 inhibitor, was used to successfully treat a patient with COVID-19 and this inhibitor has progressed to Phase II clinical trials. Eculizumab, a C5 antibody-based therapy, typically used for atypical hemolytic uremic syndrome, was reported to have been used to treat 4 COVID-19 patients. This anti-C5 treatment was carried out in combination with antiviral therapy, anticoagulant therapy, hydroxychloroquine, cephalosporin and vitamin C. Another study that employed IFX-1, an inhibitor of C5a, has progressed to Phase II/III clinical trials. In spite of the demand for an effective therapy, caution is relayed to clinicians whilst engaging in readily available literature on SARS-CoV2, for a critical examination is required before its application to the clinic. In addition to discovering suitable therapies that would curb complement-mediated inflammation, another focus would be to identify robust biomarkers to help identify patients who are likely to progress to severe disease and in determining a window for therapeutic intervention. Taking into account that the complement, by default, is a protector against pathogens, the involvement of host factors in disease progression also highlights the need for genetic studies in the population to ascertain individuals who could be considered at risk of developing severe disease. 

Snapshots into the arena of pathogen biology highlights gaps in our knowledge and emphasises the need to view infectious diseases like COVID-19 from a damage-response framework (DRF), where the host immune response needs to be included in the outcome of viral pathogenesis. This could help in understanding severe disease states, particularly where the virus is merely an initiator of severe disease and the host immune response is the culprit that brings about tissue and organ damage. Ultimately, this conceptual tool will assist clinicians and scientists alike, with observations from the clinics to the bench side, making the management of infections in an integrated manner, a reality, and is therefore an urgent need of the hour.