The COVID-19 pandemic: a global health crisis

Abstract

The novel coronavirus SARS-CoV-2 was identified as the causative agent for a series of atypical respiratory diseases in the Hubei Province of Wuhan, China in December of 2019. The disease SARS-CoV-2, termed COVID-19, was officially declared a pandemic by the World Health Organization on March 11, 2020. SARS-CoV-2 contains a single-stranded, positive-sense RNA genome surrounded by an extracellular membrane containing a series of spike glycoproteins resembling a crown. COVID-19 infection results in diverse symptoms and morbidity depending on individual genetics, ethnicity, age, and geographic location. In severe cases, COVID-19 pathophysiology includes destruction of lung epithelial cells, thrombosis, hypercoagulation, and vascular leak leading to sepsis. These events lead to acute respiratory distress syndrome (ARDS) and subsequent pulmonary fibrosis in patients. COVID-19 risk factors include cardiovascular disease, hypertension, and diabetes, which are highly prevalent in the United States. This population has upregulation of the angiotensin converting enzyme-2 (ACE2) receptor, which is exploited by COVID-19 as the route of entry and infection. Viral envelope proteins bind to and degrade ACE2 receptors, thus preventing normal ACE2 function. COVID-19 infection causes imbalances in ACE2 and induces an inflammatory immune response, known as a cytokine storm, both of which amplify comorbidities within the host. Herein, we discuss the genetics, pathogenesis, and possible therapeutics of COVID-19 infection along with secondary complications associated with disease progression, including ARDS and pulmonary fibrosis. Understanding the mechanisms of COVID-19 infection will allow the development of vaccines or other novel therapeutic approaches to prevent transmission or reduce the severity of infection.

Keywords: ARDS; COVID-19; GTPases; genetics; pulmonary fibrosis.

Fig. 1.

Biological effects of COVID-19 infection on angiotensin-converting enzyme 2 (ACE2) receptor and GTPase signaling pathways. The COVID-19 virus can bind and interact with both shed ACE2 and the cell membrane-bound ACE2 receptor. COVID-19 particles utilize and degrade membrane bound ACE2 receptors to gain entry into host cells. Virus particles also bind shed ACE2 causing a reduction in free ACE2 thus preventing the hydrolysis of ANG I/II into ANG-(1-9)/ANG-(1-7), which results in an imbalanced renin-angiotensin system that becomes skewed toward the ANG II/angiotensin type 1 receptor (AT₁R) axis. COVID-19 produces an inflammatory response, i.e., the cytokine storm, which triggers cellular activation through cytokine receptors (CRs). Upon infection, these interactions favor detrimental complications such as acute respiratory distress syndrome (ARDS)/pulmonary fibrosis, vasoconstriction and alters cytoskeletal dynamics including cell proliferation, migration, and cytoskeletal composition. Intracellular elements such as Abelson murine leukemia viral oncogene homolog 1 kinase and Rho GTPase-associated proteins play a significant role in controlling polymerization of F-actin, maintaining the density of the extracellular matrix (ECM), and modulating myofibroblast proliferation, and the development of pulmonary fibrosis.