Preventing the development of severe COVID-19 by modifying immunothrombosis

Abstract

Background: COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS.

Main body: The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail.

Keywords: COVID-19; Respiratory infection; SARS-CoV-2; Treatment.

Graphical abstract

Fig. 1

The pathophysiology of COVID-19 ARDS. Initial infection and activation of type 2 alveolar cells and alveolar macrophages by SARS-CoV-2 results in the secretion of IL-6, PICs, NO and several chemokines which activate vascular endothelial cells platelets and neutrophils ultimately forming a platelet neutrophil complex. The interplay between vascular endothelial cells activated platelets and activated primed neutrophils produces a highly coagulative and inflammatory state described as immunothrombosis. The translocation of neutrophils and platelets into the pulmonary microvasculature results in severe epithelial layer damage alveolar fibrin deposition and the formation of microthrombi. The translocation of NET producing neutrophils into alveoli and lung interstitium coupled with their delayed apoptosis results in the development cytokine storm producing extreme tissue damage and often fatal lung dysfunction created by several feedforward loops involving interplay between PICS DAMPS ROS, activation of the NLRP3 inflammasome activation, alveolar macrophage pyroptosis, influx of inflammatory bone derived monocytes and necroptosis.

Fig. 2

The effects of vitamin D on the immune system. Vitamin D inhibits B cell proliferation differentiation and immunoglobulin secretion. Vitamin D also suppresses T cell proliferation, TH17 differentiation increases levels of regulatory T cells and induces a tolerogenic Th2 phenotype. The sum of these effects is reduced levels of interleukin (IL)-17, IL-21 and IL-23 and increased levels of IL-10. Vitamin D also inhibits the maturation of dendritic cells and inhibits the production of pro inflammatory cytokines and chemokines from monocytes and macrophages reducing plasma levels of TNF-alpha, IL-1, IL-6, IL-12 and IL-8. In addition, Vitamin D activity stimulates the production of beta defensins and cathelicidin in monocytes and macrophages following pathogen invasion with forms an essential role in the anti-viral response.

Fig. 3

The effects of Vitamin C on the immune system. Vitamin C enhances the activity of TET enzymes and Jumonji C domain-containing histone demethylases (JHDMs) thereby decreasing rates of DNA and histone methylation respectively and prevents the hyperactivity of HIF 1 alpha. The net effect of these actions involves increased macrophage phagocytosis decreased neutrophil necrosis and the differentiation of T cells into a TH2 phenotype increases levels of regulatory T cells and inhibits naive T cell differentiation into a Th17 phenotype. Vitamin C is needed for memory CD8 and CD4 T cell formation and optimal T lymphocyte function. Vitamin C supplementation also reduces IL-6 and MCP-1 production by macrophages and dendritic cells while inhibiting dendritic cell maturation.