The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach

Abstract

In this paper, a model is proposed of the pathophysiological processes of COVID-19 starting from the infection of human type II alveolar epithelial cells (pneumocytes) by SARS-CoV-2 and culminating in the development of ARDS. The innate immune response to infection of type II alveolar epithelial cells leads both to their death by apoptosis and pyroptosis and to alveolar macrophage activation. Activated macrophages secrete proinflammatory cytokines and chemokines and tend to polarise into the inflammatory M1 phenotype. These changes are associated with activation of vascular endothelial cells and thence the recruitment of highly toxic neutrophils and inflammatory activated platelets into the alveolar space. Activated vascular endothelial cells become a source of proinflammatory cytokines and reactive oxygen species (ROS) and contribute to the development of coagulopathy, systemic sepsis, a cytokine storm and ARDS. Pulmonary activated platelets are also an important source of proinflammatory cytokines and ROS, as well as exacerbating pulmonary neutrophil-mediated inflammatory responses and contributing to systemic sepsis by binding to neutrophils to form platelet-neutrophil complexes (PNCs). PNC formation increases neutrophil recruitment, activation priming and extraversion of these immune cells into inflamed pulmonary tissue, thereby contributing to ARDS. Sequestered PNCs cause the development of a procoagulant and proinflammatory environment. The contribution to ARDS of increased extracellular histone levels, circulating mitochondrial DNA, the chromatin protein HMGB1, decreased neutrophil apoptosis, impaired macrophage efferocytosis, the cytokine storm, the toll-like receptor radical cycle, pyroptosis, necroinflammation, lymphopenia and a high Th17 to regulatory T lymphocyte ratio are detailed.

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

Graphical abstract

Fig. 1

Pattern Recognition receptors involved in detecting RNA viruses. Adapted from “Coronavirus Replication Cycle”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates. The presence of invading RNA viruses is detected by a family of Toll like receptors (TLRs) RIG like receptors and NOD-like receptors. From the perspective of coronavirus recognition, the important TLRs are TLR-7 and 3 which recognise single stranded RNA and the dimers of positive and negative sense RNA formed during coronavirus replication. TLR 3 and 7 are located in late endosomes which maximises viral interaction while denying the pathogen's access to the cytoplasm and nucleus. Activation of these pattern recognition receptors results in the transcription of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and INF5 leading to the production of PICs inducible nitric oxide prostaglandins and a large number of chemokines. The presence of coronavirus RNA is also recognised by the retinoic acid-inducible gene I (RIG-)-like receptors RIG-1 and MDA5 which are located in the cytoplasm. The activation of either PPR results in the assembly of a protein complex known as MAVS which acts as a signal relay to trigger the activation of INF-3 and INF-7 leading to the production of type 1 II and III interferons. There is also evidence to suggest that coronavirus activate nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) leading to the assembly of the NLRP3 inflammasome and the resultant production of interleukin (IL)-18 and IL-1. There is evidence that SARSCoV-2 inhibits interferon via the production of the non-structural proteins ORF3a and nsp-3 leading to a muted immune response and enhanced viral replication.

Fig. 2

The development of immunothrombosis. Platelets activated by thrombin and or PICs initiate (PAR)–mediated signalling further increasing levels of PICs VWF and TF coupled with suppression of suppression of thrombomodulin. Platelet activation also results in increased expression of P-selectin, CD40 PF4 and a range of surface adhesion receptors ultimately recruiting neutrophils to form platelet neutrophil complexes. NET secretion by neutrophils contributes to an increased coagulation stimulate increased levels of platelet activation, aggregation and TF mediated activation of thrombin. In addition, histones play an important role in promoting thrombin generation and inhibiting protein C-mediated anticoagulant responses. PICs also play a role in the development of coagulopathy by inhibiting the protein C-protein S-thrombomodulin pathway and increasing the production of PAI-1. The combination of a hyperactivated coagulation cascade and the inhibition of anti-coagulant pathways, such as the protein C-protein S-thrombomodulin pathway and inhibition of the fibrinolytic system is characteristic of DIC. This state is also the source of micro emboli and excessive alveolar fibrin deposition in ARDS.

Fig. 3

The physical and immunological landscape of the lung tissue in ARDS. Initial infection and activation of type 2 alveolar cells and alveolar macrophages results in the secretion of IL-6, PICs and a wide range of chemokines which activate vascular endothelial cells and recruit peripheral activated NET producing neutrophils. Mechanistically this is achieved via the formation of platelet neutrophil complexes which become sequestrated in the lung microcapillaries creating a hyper coagulant and highly inflammatory environment within these blood vessels and the wider pulmonary circulation. The entry of neutrophils into the lung coupled with their prolonged survival results in the development of a cytokine storm with extreme tissue damage and lung dysfunction fuelled by an interplay between PICs DAMPs ROS, NLRPs activation, macrophage pyroptosis, influx of inflammatory monocytes and necroptosis.