- Levels of C5a circulating in COVID-19 patient plasma increase proportionally with the severity of the disease
- C5a and its receptor C5aR1, are also abundant in the lungs of severe COVID-19 patients
- C5aR1 promotes inflammation; its blockade using a monoclonal antibody, avdoralimab, prevents myeloid cell activation and migration in vitro, and acute lung injury in vivo
- The latest results of this research, authored by Julien Carvelli et al. are published today in Nature
COVID-19 is an infectious disease caused by the novel coronavirus SARS-CoV-2. While most infected patients present mild symptoms, 15% progress to severe pneumonia, and around 5% to acute respiratory distress syndrome (ARDS). It is now well established that these severe cases are linked to an excessive inflammatory response, associated to what is referred to as a “cytokine storm”. To understand the immune response during disease progression, the Marseille-based exploratory research program EXPLORE COVID-19 has undertaken a longitudinal analysis of immune parameters in a cohort of 82 individuals at various stages of COVID-19 severity.
C5a/C5aR1: promoting inflammation in COVID-19
In agreement with previous studies, the scientists found that the disease severity is associated with a global increase in the amounts of inflammatory cytokines among circulating factors. Interestingly, levels of the complement factor C5a, already known for having a role in lung inflammation and injury, increase proportionally to COVID-19 severity. This is true not only in peripheral blood, but also inside the lungs, where its receptor, C5aR1, is highly expressed at the surface of myeloid cells (neutrophils and monocytes). The study further reveals that the C5a/C5aR1 axis triggers an inflammatory response in vitro, and provides evidence suggesting that C5a promotes the migration into the lungs of pro-inflammatory, C5aR1-expressing myeloid cells in patients.
Targeting C5aR1: blocking the trigger with avdoralimab
To block the pro-inflammatory role of the C5a/C5aR1 axis in the context of COVID-19, the scientists used a monoclonal antibody against human C5aR1 called avdoralimab. Also developed for use in oncology, this antibody prevents binding of C5a to its receptor. In vitro, avdoralimab inhibits the activation and migration of neutrophils, as well as the release of inflammatory cytokines by monocytes. Importantly, in vivo, the antibody attenuates inflammation in mice that express human C5aR1 and display C5a-induced acute lung injury (the antibody inhibits infiltration of neutrophils and monocytes, prevents albumin release in the lungs and limits histopathological features of acute lung injury). These promising results are further supported by other studies that suggest that targeting the C5a/C5aR1 axis might indeed display beneficial effects in COVID-19.
Beyond the lungs, preventing COVID-19-associated endothelialitis
Increasing evidence suggests that the SARS-CoV-2 virus spreads, in the most severe COVID-19 cases, beyond the lung epithelial barrier and into the vascular system, where it causes the inflammation of endothelial cells, or endothelialitis. The scientists report, in COVID-19 patients, cases of obliterating endarteritis – an inflammation of the inner lining of an artery – associated with an accumulation of macrophages expressing the C5aR1 receptor around the arteries and in the thrombus. This result, together with the high levels of circulating C5a in symptomatic COVID-19 patients, suggests a role for the C5a/C5aR1 axis in the transition from an epithelial disease in the lungs to a diffuse endothelial disease. It further supports the use of an anti-C5aR1 for the treatment of severe COVID-19 patients. Based on these findings, a randomized, double-blind Phase II clinical trial named FORCE (FOR COVID-19 Elimination) was initiated to explore the effects of avdoralimab in COVID-19 patients with severe pneumonia.
Figure. Progression towards severe COVID-19 is associated with a transition from an epithelial disease to an endothelial disease.
These findings result from the concerted efforts of several Marseille-based players involved in the EXPLORE COVID-19 project, including the emergency, intensive care and internal medicine units at La Timone, Nord and Laveran Hospitals, the MI/AP-HM immunoprofiling laboratory at La Timone Hospital, the research institute Centre d’Immunologie de Marseille-Luminy (CIML) and the biotech company Innate Pharma. Together and within the Marseille Immunopole cluster, they were able to rapidly assemble their strengths in the emergency context set by the current pandemic, to contribute to the global efforts to characterize and understand the disease, and to provide a promising therapeutic avenue for severe COVID-19 patients.
Julien Carvelli, Olivier Demaria, Frédéric Vély, Luciana Batista, Nassima Chouaki Benmansour, Joanna Fares, Sabrina Carpentier, Marie-Laure Thibult, Ariane Morel, Romain Remark, Pascale André, Agnès Represa, Christelle Piperoglou, the Explore COVID-19 IPH group, the Explore COVID-19 Marseille Immunopole group, Pierre Yves Cordier, Erwan Le Dault, Christophe Guervilly, Pierre Simeone, Marc Gainnier, Yannis Morel, Mikael Ebbo, Nicolas Schleinitz, Eric Vivier. Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis. Nature 2020. https://www.nature.com/articles/s41586-020-2600-6