A Review: Does Complement or the Contact System Have a Role in Protection or Pathogenesis of COVID-19?

COVID-19 presentation may include a profound increase in cytokines and associated pneumonia, rapidly progressing to acute respiratory distress syndrome (ARDS). This so-called cytokine storm often leads to refractory edema, respiratory arrest, and death. At present, anti-IL-6, antiviral therapy, convalescent plasma, hydroxychloroquine, and azithromycin among others are being investigated as potential treatments for COVID-19. As the disease etiology and precise therapeutic interventions are still not definitively defined, we wanted to review the roles that complement and the contact system may have in either the treatment or pathogenesis of the disease.

We searched the recent literature (PubMed) on complement and coronavirus; contact system and coronavirus; bradykinin and coronavirus; and angiotensin receptor and coronavirus. The manuscript complies with ethics guidelines and was deemed exempt from institutional review board approval according to Human Subjects Protection Office guidelines.

Mouse models are available for the study of coronavirus and complement. Although complement is effective in protecting against many viruses, it does not seem to be protective against coronavirus. C3 knockout mice infected with SARS-CoV had less lung disease than wild-type mice, suggesting that complement may play a role in coronavirus pathogenesis. Some evidence suggests that the observed pulmonary edema may be bradykinin-induced and could be the reason that corticosteroids, antihistamines, and other traditional interventions for edema are not effective. Angiotensin-converting enzyme 2 (ACE2) is a co-receptor for SARS-CoV-2, and studies thus far have not concluded a benefit or risk associated with the use of either ACE-inhibitors or angiotensin receptor antagonists. Activation of complement and the contact system, through generation of bradykinin, may play a role in the SARS-CoV-2-induced pulmonary edema, and our search suggests that further work is necessary to confirm our suspicions.