COVID-19 News: Inhibition Of The Lectin Pathway Of Complement Activation Reduces Acute Respiratory Distress Syndrome Severity In SARS-CoV-2 Infections

COVID-19 News: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a profound impact on global health and continues to challenge the scientific and medical communities. The severity of this viral infection ranges from mild symptoms to life-threatening complications, such as acute respiratory distress syndrome (ARDS). The University of Cambridge in the United Kingdom, the Mario Negri Institute for Pharmacological Research in Italy, and Omeros Corporation in Seattle, USA, have collaborated on a groundbreaking study to investigate a potential therapeutic avenue to mitigate the severity of COVID-19-related ARDS. Their research centers on inhibiting the lectin pathway of complement activation, particularly targeting the enzyme MASP-2 with an inhibitory antibody named HG4.


 
COVID-19: A Global Health Crisis
The outbreak of COVID-19 has evolved into a global health crisis, affecting people of all ages but posing a particularly high risk to the elderly and individuals with underlying medical conditions as covered in various past studies and COVID-19 News reports. The virus continues to mutate, leading to the emergence of new variants, some of which exhibit increased transmissibility and the potential to evade immunity generated through vaccination or previous infection. The primary modes of transmission include respiratory droplets and aerosols, with infected individuals experiencing a wide range of disease severity, from mild to moderate, severe, and critical. As the infection progresses, patients can develop acute respiratory distress syndrome, a condition characterized by severe hypoxemia, decreased lung compliance, and high vascular permeability.
 
Beyond the respiratory symptoms, COVID-19 can manifest with various neurological symptoms, including headache, ischemic stroke, seizures, delirium, anosmia, and encephalopathy. In severe cases, cortical signal alteration, loss of white matter, and axonal injury have also been reported. These neurological manifestations underscore the virus's ability to impact multiple organ systems, including the central nervous system (CNS).
 
Microglia: The Guardians of Brain Health
Within the CNS, microglial cells play a vital role in maintaining brain health and responding to infections and injuries. These brain-resident macrophages are involved in processes such as axonal pruning, cellular debris removal, and the release of cytokines and chemokines to attract immune cells to sites of infection or injury. The morphological characteristics of microglia can change to reflect their activation status, with homeostatic microglia appearing thin and ramified, while reactive microglia exhibit a hypertrophic shape with increased size and ramification. These cells are crucial in the clearance of pathogens, tissue repair, and the modulation of the local immune response.
 
The Complement System: A Double-Edged Sword
The complement system is a fundamental component of the innate immune response, involved in the recognition, opsonization, and elimination of various pathogens, including viruses. It consists of three activation pathways: the classical pathway (CP), the lectin pathway (LP) , and the alternative pathway (AP). The CP is initiated by C1q binding to immune complexes, leading to the autoactivation of CP-specific serine proteases, C1r and C1s. The LP is activated when specific recognition components, including mannan-binding lectin (MBL) and ficolins, bind to their ligands, triggering the activation of LP serine proteases, notably MASP-2, which can cleave C4 and C2 to form the C3 convertase C4bC2a. The AP serves as an amplification loop for both the CP and the LP, enhancing complement activation. Activation of the complement cascade ultimately results in the cleavage of C3 and C5, generating the anaphylatoxins C3a and C5a, which promote inflammation and leukocyte infiltration.
 
The Complement System's Role in COVID-19
Complement activation has been strongly linked to the development of ARDS and respiratory failure during viral pneumonia, including SARS-CoV-2 infection. Post-mortem biopsies of COVID-19 patients revealed the presence of thrombotic microangiopathies (TMAs) and the deposition of complement activation products, such as C5b-9, C3d, C4d, and MASP-2, in affected tissues and organs. Additionally, elevated levels of complement C5a and soluble C5b-9 were detected in the sera of COVID-19 patients, indicating ongoing complement activation during SARS-CoV-2 infection.
 
These findings have spurred investigations into complement therapeutics as potential treatments for critically ill COVID-19 patients. Narsoplimab (OMS721), a human immunoglobulin gamma 4 (IgG4) monoclonal antibody targeting MASP-2 to inhibit LP activity, showed significant benefits in a phase 2 clinical study, improving lung function, laboratory markers, and overall disease severity.
 
Inhibition of MASP-2 and Reduction of ARDS Severity
Despite extensive research, there are limited therapeutic options for COVID-19 patients suffering from ARDS. The study aimed to fill this gap by assessing the therapeutic potential of inhibiting MASP-2, a key enzyme in the lectin pathway, using the inhibitory antibody HG4 in a mouse model of SARS-CoV-2 infection.
 
In the study, mice were infected with the Beta variant of SARS-CoV-2, and some were treated with HG4, while others received isotype control antibodies. The results were striking – mice treated with HG4 exhibited reduced disease severity, improved survival rates, and decreased lung injury scores, including reduced alveolar inflammatory cell infiltration, alveolar edema, and alveolar hemorrhage.
 
These findings were further supported by a reduction in the pro-inflammatory activation of brain microglia in HG4-treated mice, indicating the ameliorating effect of MASP-2 inhibition on the severity of COVID-19 pathology.
 
The Mechanism of Action
The study highlights that MASP-2 inhibition with HG4 primarily acts on the pro-inflammatory activity in response to the virus, rather than directly affecting the virus itself. It prevents the shift in microglial activation toward hypertrophic reactive microglia, which can lead to neurotoxicity and other adverse effects in the CNS. This mechanism may hold promise not only for ARDS but also for a range of CNS disorders associated with microglial activation.
 
The Predominance of the Lectin Pathway
The research findings emphasize the key role of the lectin pathway in driving complement-dependent inflammatory responses in COVID-19. Even in the absence of detectable antibody responses to SARS-CoV-2 infection in the early stages of the disease, the lectin pathway is highly activated. This suggests that the lectin pathway, rather than the classical pathway, primarily initiates complement activation in response to SARS-CoV-2 infection. The study points to the lectin pathway as the dominant driver of complement-dependent inflammatory pathology in COVID-19, with subsequent amplification through the alternative pathway.
 
Conclusion
The study findings have shed light on a potential therapeutic approach for COVID-19-related ARDS. Inhibiting the lectin pathway of complement activation, with a specific focus on the enzyme MASP-2 using the HG4 antibody, has shown promising results in reducing disease severity, improving survival rates, and mitigating pro-inflammatory responses in the CNS.
 
As the COVID-19 pandemic continues to evolve, these findings may open new avenues for treatment and further our understanding of the complex interactions between the complement system, the immune response, and the virus. This research not only offers hope for those currently affected by severe COVID-19 but also provides insights that may be applicable to other diseases with complement-mediated pathologies.
 
The study findings were published in the peer reviewed journal: The Journal of Infectious Diseases. (Oxford).
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad462/7329543
 
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