Pathophysiology of SARS-CoV-2 Infection and COVID-19

A detailed understanding of the pathophysiologic mechanisms of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and Coronavirus disease 2019 (COVID-19) is vital for improving patient management - to facilitate prompt recognition of progression to severe disease and effective therapeutic strategies. This chapter summarizes the underlyingpathophysiology in the lungs and other organs of COVID- 19 patients. The roles of the cytokine storm culminating in exaggerated inflammatory responses and formation of neutrophil extracellular traps (NETs) are discussed. Pathological features of the various stages from the onset of COVID-19 are outlined - progressing from early mild infection to severe clinical illness to the critically ill phase. © 2023 by World Scientific Publishing Co. Pte. Ltd.

Effect of miRNAs, Proinflammatory Cytokines and ACE2 in COVID-19 Pathophysiology

Background: Angiotensin-converting enzyme 2 (ACE2) is the main cellular receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and acts as a pro-inflammatory mediator of Coronavirus disease (COVID-19). The clinical outcome of SARS-CoV-2 infection is influenced by the pro-inflammatory mediators. The specific microRNAs (miRNAs) influence the ACE2 expression and are accountable for the increased circulatory pro-inflammatory mediator levels. Thus, host factors play a crucial role in COVID-19 pathophysiology. The pathogenesis of COVID-19 disease is not well understood. Hence we comprehended the role of miRNAs, pro-inflammatory cytokines, and ACE2 genes in COVID-19 pathophysiology. Method(s): We utilized multiple databases, specifically EMBASE, PubMed (Medline), and Google Scholar, for our search. Discussion(s): SARS-CoV-2 genes could be the target of host miRNAs. The miRNAs regulate the expression of ACE2 in various organs, including the kidney, heart, blood vessels, and lung. ACE2 acts as a pro-inflammatory mediator of SARS-CoV-2 associated disease. Pro-inflammatory cytokines (IL-6, IL-1beta, and TNF) have been associated with severe COVID-19 disease. Hence variation in expression of miRNAs would influence the regulation of COVID-19 pathophysiology. The clinical outcomes of COVID-19 are variable which could be linked with the difference in binding of host miRNA to the target genes. Conclusion(s): Correlation of these genes with severe or critical stages of patients will provide bio-markers for the severity of lung inflammation which would be useful in the rapid identification of patients in need of hospital admission. Analysis of the relationship between the miRNAs and ACE2 will be helpful in designing anti-miR therapy for ACE2-related SARS-CoV-2 infection.Copyright © 2021 Bentham Science Publishers.

MMP-2 and MMP-9 levels in plasma are altered and associated with mortality in COVID-19 patients.

Respiratory symptoms are one of COVID-19 manifestations, and the metalloproteinases (MMPs) have essential roles in the lung physiology. We sought to characterize the plasmatic levels of matrix metalloproteinase-2 and 9 (MMP-2 and MMP-9) in patients with severe COVID-19 and to investigate an association between plasma MMP-2 and MMP-9 levels and clinical outcomes and mortality. MMP-2 and MMP-9 levels in plasma from patients with COVID-19 treated in the ICU (COVID-19 group) and Control patients were measured with the zymography. The study groups were matched for age, sex, hypertension, diabetes, BMI, and obesity profile. MMP-2 levels were lower and MMP-9 levels were higher in a COVID-19 group (p < 0.0001) compared to Controls. MMP-9 levels in COVID-19 patients were not affected by comorbidity such as hypertension or obesity. MMP-2 levels were affected by hypertension (p < 0.05), but unaffected by obesity status. Notably, hypertensive COVID-19 patients had higher MMP-2 levels compared to the non-hypertensive COVID-19 group, albeit still lower than Controls (p < 0.05). No association between MMP-2 and MMP-9 plasmatic levels and corticosteroid treatment or acute kidney injury was found in COVID-19 patients. The survival analysis showed that COVID-19 mortality was associated with increased MMP-2 and MMP-9 levels. Age, hypertension, BMI, and MMP-2 and MMP-9 were better predictors of mortality during hospitalization than SAPS3 and SOFA scores at hospital admission. In conclusion, a significant association between MMP-2 and MMP-9 levels and COVID-19 was found. Notably, MMP-2 and MMP-9 levels predicted the risk of in-hospital death suggesting possible pathophysiologic and prognostic roles.

COVID-19 pathophysiology and pharmacology: what do we know and how did Canadians respond? A review of Health Canada authorized clinical vaccine and drug trials.

Coronavirus disease 2019 (COVID-19) has resulted in the death of over 18 000 Canadians and has impacted the lives of all Canadians. Many Canadian research groups have expanded their research programs to include COVID-19. Over the past year, our knowledge of this novel disease has grown and has led to the initiation of a number of clinical vaccine and drug trials for the prevention and treatment of COVID-19. Here, we review SARS-CoV-2 (the coronavirus that causes COVID-19) and the natural history of COVID-19, including a timeline of disease progression after SARS-CoV-2 exposure. We also review the pathophysiological effects of COVID-19 on the organ systems that have been implicated in the disease, including the lungs, upper respiratory tract, immune system, central nervous system, cardiovascular system, gastrointestinal organs, the liver, and the kidneys. Then we review general therapeutics strategies that are being applied and investigated for the prevention or treatment of COVID-19, including vaccines, antivirals, immune system enhancers, pulmonary supportive agents, immunosuppressants and (or) anti-inflammatories, and cardiovascular system regulators. Finally, we provide an overview of all current Health Canada authorized clinical drug and vaccine trials for the prevention or treatment of COVID-19.

Phosphatidylserine inside out: a possible underlying mechanism in the inflammation and coagulation abnormalities of COVID-19.

The rapid ability of SARS-CoV-2 to spread among humans, along with the clinical complications of coronavirus disease 2019-COVID-19, have represented a significant challenge to the health management systems worldwide. The acute inflammation and coagulation abnormalities appear as the main causes for thousands of deaths worldwide. The intense inflammatory response could be involved with the formation of thrombi. For instance, the presence of uncleaved large multimers of von Willebrand (vWF), due to low ADAMTS13 activity in plasma could be explained by the inhibitory action of pro-inflammatory molecules such as IL-1ß and C reactive protein. In addition, the damage to endothelial cells after viral infection and/or activation of endothelium by pro-inflammatory cytokines, such as IL-1ß, IL-6, IFN-γ, IL-8, and TNF-α induces platelets and monocyte aggregation in the vascular wall and expression of tissue factor (TF). The TF expression may culminate in the formation of thrombi, and activation of cascade by the extrinsic pathway by association with factor VII. In this scenario, the phosphatidylserine-PtdSer exposure on the outer leaflet of the cell membrane as consequence of viral infection emerges as another possible underlying mechanism to acute immune inflammatory response and activation of coagulation cascade. The PtdSer exposure may be an important mechanism related to ADAM17-mediated ACE2, TNF-α, EGFR and IL-6R shedding, and the activation of TF on the surface of infected endothelial cells. In this review, we address the underlying mechanisms involved in the pathophysiology of inflammation and coagulation abnormalities. Moreover, we introduce key biochemical and pathophysiological concepts that support the possible participation of PtdSer exposure on the outer side of the SARS-CoV-2 infected cells membrane, in the pathophysiology of COVID-19. Video Abstract.

Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage.

COVID-19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID-19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID-19-infected patients experiencing a range of disease severities and 17 healthy controls. A large number of expressed genes, proteins, metabolites, and extracellular RNAs (exRNAs) exhibit strong associations with various clinical parameters. Multiple sets of tissue-specific proteins and exRNAs varied significantly in both mild and severe patients suggesting a potential impact on tissue function. Chronic activation of neutrophils, IFN-I signaling, and a high level of inflammatory cytokines were observed in patients with severe disease progression. In contrast, COVID-19-infected patients experiencing milder disease symptoms showed robust T-cell responses. Finally, we identified genes, proteins, and exRNAs as potential biomarkers that might assist in predicting the prognosis of SARS-CoV-2 infection. These data refine our understanding of the pathophysiology and clinical progress of COVID-19.

ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19.

The Coronavirus Disease 2019 (COVID-19) has already caused hundreds of thousands of deaths worldwide in a few months. Cardiovascular disease, hypertension, diabetes and chronic lung disease have been identified as the main COVID-19 comorbidities. Moreover, despite similar infection rates between men and women, the most severe course of the disease is higher in elderly and co-morbid male patients. Therefore, the occurrence of specific comorbidities associated with renin-angiotensin system (RAS) imbalance mediated by the interaction between angiotensin-converting enzyme 2 (ACE2) and desintegrin and metalloproteinase domain 17 (ADAM17), along with specific genetic factors mainly associated with type II transmembrane serine protease (TMPRSS2) expression, could be decisive for the clinical outcome of COVID-19. Indeed, the exacerbated ADAM17-mediated ACE2, TNF-α, and IL-6R secretion emerges as a possible underlying mechanism for the acute inflammatory immune response and the activation of the coagulation cascade. Therefore, in this review, we focus on the main pathophysiological aspects of ACE2, ADAM17, and TMPRSS2 host proteins in COVID-19. Additionally, we discuss a possible mechanism to explain the deleterious effect of ADAM17 and TMPRSS2 over-activation in the COVID-19 outcome.