[Involvement of the complement cascade in severe forms of COVID-19]. / Implication de la cascade du complément dans les formes sévères de COVID-19.

The complement system is an essential component of the innate immune system. Its excessive activation during COVID-19 contributes to cytokine storm, disease-specific endothelial inflammation (endotheliitis) and thrombosis that comes with the disease. Targeted therapies of complement inhibition in COVID-19, in particular blocking the C5a-C5aR1 axis have to be taken into account in the establishment of potential biomarkers and development of therapeutic strategies in the most severe forms of the disease.

TITLE: Implication de la cascade du complément dans les formes sévères de COVID-19. ABSTRACT: Le système du complément est un composant essentiel du système immunitaire inné. Son activation excessive au cours de la COVID-19 participe à l'orage cytokinique, à l'inflammation endothéliale (endothélite) et aux thromboses qui accompagnent la maladie. Bloquer le complément, notamment l'axe C5a-C5aR1, par des thérapies spécifiques représente un espoir thérapeutique dans les formes les plus sévères de la maladie.

Complement cascade in severe forms of COVID-19: Recent advances in therapy.

The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID-19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID-19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a-C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.

Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis.

Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic1. The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes1. Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.

Author Correction: Phosphoinositides regulate the TCR/CD3 complex membrane dynamics and activation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Phosphoinositides regulate the TCR/CD3 complex membrane dynamics and activation.

Phosphoinositides (PIs) play important roles in numerous membrane-based cellular activities. However, their involvement in the mechanism of T cell receptor (TCR) signal transduction across the plasma membrane (PM) is poorly defined. Here, we investigate their role, and in particular that of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] in TCR PM dynamics and activity in a mouse T-cell hybridoma upon ectopic expression of a PM-localized inositol polyphosphate-5-phosphatase (Inp54p). We observed that dephosphorylation of PI(4,5)P2 by the phosphatase increased the TCR/CD3 complex PM lateral mobility prior stimulation. The constitutive and antigen-elicited CD3 phosphorylation as well as the antigen-stimulated early signaling pathways were all found to be significantly augmented in cells expressing the phosphatase. Using state-of-the-art biophotonic approaches, we further showed that PI(4,5)P2 dephosphorylation strongly promoted the CD3ε cytoplasmic domain unbinding from the PM inner leaflet in living cells, thus resulting in an increased CD3 availability for interactions with Lck kinase. This could significantly account for the observed effects of PI(4,5)P2 dephosphorylation on the CD3 phosphorylation. Our data thus suggest that PIs play a key role in the regulation of the TCR/CD3 complex dynamics and activation at the PM.

Argan oil improves surrogate markers of CVD in humans.

Limited - though increasing - evidence suggests that argan oil might be endowed with potential healthful properties, mostly in the areas of CVD and prostate cancer. We sought to comprehensively determine the effects of argan oil supplementation on the plasma lipid profile and antioxidant status of a group of healthy Algerian subjects, compared with matched controls. A total of twenty healthy subjects consumed 15 g/d of argan oil - with toasted bread - for breakfast, during 4 weeks (intervention group), whereas twenty matched controls followed their habitual diet, but did not consume argan oil. The study lasted 30 d. At the end of the study, argan oil-supplemented subjects exhibited higher plasma vitamin E concentrations, lower total and LDL-cholesterol, lower TAG and improved plasma and cellular antioxidant profile, when compared with controls. In conclusion, we showed that Algerian argan oil is able to positively modulate some surrogate markers of CVD, through mechanisms which warrant further investigation.