A groundbreaking study conducted by the University of Cambridge, the Mario Negri Institute for Pharmacological Research, and Omeros Corporation has revealed a potential therapeutic avenue for mitigating the severity of COVID-19-related acute respiratory distress syndrome (ARDS). The focus of their research is on inhibiting the lectin pathway of complement activation, particularly by targeting the enzyme MASP-2 with an inhibitory antibody called HG4.
COVID-19 continues to pose risks to individuals of all age groups, with the elderly and those with underlying medical conditions being particularly vulnerable. The virus has also been mutating, giving rise to new variants that may be more transmissible and capable of evading immunity. ARDS, a condition characterized by respiratory distress, can develop in some individuals infected with COVID-19. Additionally, the virus has been observed to affect various organ systems, including the central nervous system, leading to neurological symptoms.
Microglial cells, known as the guardians of brain health, play a crucial role in maintaining brain function and responding to infections and injuries. The complement system, a component of the immune response, has been implicated in both immune defense and inflammation. The lectin pathway of complement activation, in particular, has been strongly associated with the development of ARDS and respiratory failure in viral pneumonia, including COVID-19.
Research has demonstrated a link between complement activation and the severity of COVID-19. Post-mortem biopsies of COVID-19 patients have shown the presence of complement activation products in affected tissues and organs. Furthermore, elevated levels of complement activation markers have been detected in the sera of COVID-19 patients. These findings have prompted investigations into complement therapeutics as potential treatments for critically ill individuals with COVID-19.
The recent study focused on inhibiting MASP-2, a key enzyme in the lectin pathway, using the inhibitory antibody HG4. Mice infected with the Beta variant of SARS-CoV-2 were treated with HG4 or control antibodies. The results were promising, with HG4-treated mice exhibiting reduced disease severity, improved survival rates, and decreased lung injury. Additionally, inhibiting MASP-2 had a positive impact on the activation of brain microglia, suggesting potential benefits in mitigating COVID-19 pathology in the central nervous system.
The mechanism of action of HG4 primarily involves reducing pro-inflammatory activity in response to the virus rather than directly targeting the virus itself. By preventing the activation of reactive microglia, HG4 may prevent neurotoxicity and other adverse effects in the central nervous system. This mechanism holds promise not only for ARDS but also for other central nervous system disorders associated with microglial activation.
The study’s findings emphasize the significant role of the lectin pathway in driving complement-dependent inflammatory responses in COVID-19. Even in the absence of detectable antibody responses, the lectin pathway is highly activated in the early stages of the disease. This suggests that the lectin pathway, rather than the classical pathway, is primarily responsible for initiating complement activation in response to SARS-CoV-2 infection. The study indicates that the lectin pathway is the main driver of complement-dependent inflammatory pathology in COVID-19, with amplification through the alternative pathway.
In conclusion, the study’s findings provide a potential therapeutic approach for mitigating the severity of COVID-19-related ARDS. By inhibiting the lectin pathway of complement activation, specifically targeting MASP-2 with the HG4 antibody, the researchers have demonstrated promising results in reducing disease severity and improving survival rates. This research not only offers hope for severe COVID-19 patients but also enhances our understanding of the complex interactions between the complement system, the immune response, and the virus. The findings may have broader implications for the treatment of other diseases characterized by complement-mediated pathologies.