The complement system plays a critical role in the rapid host innate immune response to bacterial, viral, and fungal infections [1]. Complement activation allows antibodies and phagocytic cells to detect and clear microbes at the site of infection and stimulates the recruitment of inflammatory cells, including macrophages, neutrophils, and mast cells [2, 3]. There are three distinct pathways through which the complement cascade can be triggered: the classical antigen–antibody complex pathway, alternative pathway, and mannose-binding lectin (MBL) pathway [1, 3]. These pathways can lead to microbe opsonization, inflammation, recruitment of immune cells, and cell lysis, and therefore must be tightly regulated given their potential to harm host tissues [3] (Fig. 1).
Coronaviruses (CoVs) are enveloped, positive-sense RNA viruses that can infect a wide range of hosts including pigs, camels, bats, cats, and humans [1]. According to the Centers for Disease Control and Prevention, seven CoVs are known to give rise to human disease. CoVs 229E, OC43, NL63, and HKU1 can cause mild upper respiratory tract symptoms, similar to the “common cold” [1, 4]. On the other hand, three CoVs recognized as SARS (severe acute respiratory syndrome)-CoV, MERS (Middle East respiratory syndrome)-CoV, and SARS-CoV-2 (COVID-19) have led to more severe clinical outcomes for infected patients [1] (Table 1). Typical symptoms induced by CoV infection include fever, headache, and cough [4]. Conversely, SARS-CoV, MERS-CoV, and COVID-19 may initially present asymptomatically, but can progress to pneumonia, shortness of breath, renal insufficiency and, in some cases, death [4]. When examining the histopathological changes that occur in pulmonary lesions of SARS-CoV patients, studies have described the presence of a nonspecific innate immune response and swelling [1, 4]. The severe inflammation that accompanies SARS-CoV infection can also lead to lung tissue necrosis and alveolar hyperplasia [1]. Such substantial damage to the lung epithelium suggests that the inflammatory response induced by SARS-CoV can significantly contribute to the course of the disease. Specifically, C3a and C5a, pro-inflammatory molecules generated by the complement system, can trigger inflammatory cell infiltration and contribute to lung injury [1]. Additionally, mounting evidence indicates that SARS-CoV infection can activate the complement cascade systemically, thus affecting other organs and influencing disease exacerbation [2].
Table 1 Pathogenicity and transmission of three coronavirus (CoV) outbreaks Interestingly, the role of the complement system in SARS-CoV pathogenesis is considered controversial. In particular, multiple studies have investigated the importance of the MBL pathway of complement in the context of SARS-CoV infection; however, the results were contradictory and inconclusive. One study, published by Ip et al., demonstrated that patients with low serum MBL levels were at higher risk of becoming infected with SARS-CoV, suggesting that complement activation via MBL may be critical in protecting the host from SARS-CoV infection [5]. Conversely, Yuan et al. showed that there is no clear link between patients’ MBL genotypes/haplotypes and their susceptibility to SARS-CoV infection and disease [6]. Furthermore, some in vitro studies have revealed that MBL does not consistently bind to the SARS-CoV Spike protein, highlighting the uncertainty surrounding SARS-CoV recognition by complement [7]. Unfortunately, in vivo studies investigating the relationship between SARS-CoV pathogenesis and complement are lacking. While the scientific literature on MERS-CoV pathogenesis and complement response is not as extensive as that on SARS-CoV, studies have shown that inhibiting the complement system by blocking the C5a/C5a receptor can reduce MERS-CoV-mediated lung tissue damage in infected mice [8, 9]. Collectively, the discrepancies in the results of these studies reveal that complement response to CoV, SARS-CoV in particular, is largely unclear, as it may be protective or pathogenic [10].
Studies exploring the relationship between SARS-CoV infection and complement have demonstrated that complement activation can lead to disease exacerbation. Indeed, Gralinski et al. reported that intranasal infection of mice with mouse-adapted SARS-CoV resulted in activation of the complement cascade systemically and led to immune cell infiltration in the lung as early as 1 day post-infection [2]. In order to determine whether complement activation is involved in the pathogenic outcomes observed in patients infected with SARS-CoV, this study used mice genetically null for the gene C3 (C3−/−) [2]. C3 is the major component of the complement system and is involved in all three complement pathways (Fig. 1). The study concluded that C3−/− mice infected with SARS-CoV experienced less respiratory illness compared with infected wild-type mice [2]. Additionally, infected C3−/− mice had decreased numbers of inflammatory neutrophils and monocytes, immune cells known to be implicated in CoV pathogenesis, recruited to their lungs. Finally, C3-deficient mice had lower serum and lung tissue cytokine levels than SARS-CoV-infected controls [2]. Collectively, these findings reveal that without complement, SARS-CoV is unable to induce as robust an inflammatory response as it does in wild-type mice. The exact mechanism through which SARS-CoV is recognized by complement is still under investigation; however, the results of this study suggest that SARS-CoV infection activates complement, which subsequently contributes to disease. Additionally, there is evidence that complement response to SARS-CoV also leads to potent inflammation systemically, as demonstrated by complement protein deposition in the kidneys [2]. Importantly, since the loss of C3 had no influence on the viral titer levels in mouse lung tissue, it suggests that the complement system may not be necessary for protection against SARS-CoV infection [2].
A recent manuscript by Campbell and Kahwash in Circulation called for initiating a trial of complement inhibition with the use of eculizumab, a monoclonal antibody against C5. The clinical observations of life-threatening COVID-19 include elevated lactate dehydrogenase (LDH), d-dimer, and bilirubin, decreased platelets, anemia, and renal and cardiac involvement, all of which are also seen in atypical hemolytic uremic syndrome (aHUS). Excessive complement activation leading to diffuse thrombotic microangiopathy (TMA) is the pathogenesis of aHUS. The end-organ dysfunction and the findings above, which respond to eculizumab, suggest that this intervention may also be successful in severe COVID-19 [11].
Overall, a better understanding of how complement interacts with SARS-CoV-2 and affects COVID-19 pathogenesis can lead to the development of more effective therapeutics for infected patients. If the complement system does in fact promote disease progression post-CoV infection, then inhibiting complement signaling may be an effective approach. In fact, antibodies against C5/C5a can potentially help reduce the pulmonary dysfunction observed in COVID-19 patients (Fig. 1). Thus, further investigation is needed in order to determine the mechanisms that govern SARS-CoV-2 pathogenesis and whether the complement system is associated with disease exacerbation.