COVID-19 Mechanisms in the Human Body-What We Know So Far

Abstract

More than one and a half years have elapsed since the commencement of the coronavirus disease 2019 (COVID-19) pandemic, and the world is struggling to contain it. Being caused by a previously unknown virus, in the initial period, there had been an extreme paucity of knowledge about the disease mechanisms, which hampered preventive and therapeutic measures against COVID-19. In an endeavor to understand the pathogenic mechanisms, extensive experimental studies have been conducted across the globe involving cell culture-based experiments, human tissue organoids, and animal models, targeted to various aspects of the disease, viz., viral properties, tissue tropism and organ-specific pathogenesis, involvement of physiological systems, and the human immune response against the infection. The vastly accumulated scientific knowledge on all aspects of COVID-19 has currently changed the scenario from great despair to hope. Even though spectacular progress has been made in all of these aspects, multiple knowledge gaps are remaining that need to be addressed in future studies. Moreover, multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have emerged across the globe since the onset of the first COVID-19 wave, with seemingly greater transmissibility/virulence and immune escape capabilities than the wild-type strain. In this review, we narrate the progress made since the commencement of the pandemic regarding the knowledge on COVID-19 mechanisms in the human body, including virus-host interactions, pulmonary and other systemic manifestations, immunological dysregulations, complications, host-specific vulnerability, and long-term health consequences in the survivors. Additionally, we provide a brief review of the current evidence explaining molecular mechanisms imparting greater transmissibility and virulence and immune escape capabilities to the emerging SARS-CoV-2 variants.

Keywords: COVID-19; SARS-CoV-2; immune response; organotropism; pathogenesis.

Figure 1

The symptomatology of coronavirus disease 2019 (COVID-19). (The onset of the clinical symptoms occurs in average 5–6 days after exposure, and normally, those with mild symptoms recover within 2 weeks; however, in severe cases, the recovery may extend up to 6 weeks. Persistence of the disease or, after complete recovery, emergence of new ailments, together known as “long COVID” may occur in some patients. The “long COVID” is chiefly characterized by the presence of fatigue, headache, dyspnea, and anosmia, which may persist for 4–12 weeks.

Figure 2

A schema for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into human cells. [Entry of SARS-CoV-2 into human cells is mediated by a cell surface receptor angiotensin-converting enzyme-2 (ACE2). ACE2 binds to receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein. Furthermore, to enter into the host cell, the priming of the viral spike protein (S) for its fusion to host cell membrane is done by host cell proteases, which involves cleavage of ‘S’ protein by the serine proteases, transmembrane serine protease 2 (TMPRSS2) or Cathepsin B or L (CTS-B or -L), and furin present in the host cell membrane. CTS-B or -L) acts primarily inside the endosomes. Furin cleavage site (PRRAR), present at the intersection of S1 and S2, is considered an evolutionary gain in SARS-CoV-2.

Figure 3

Expression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host cell entry receptor and entry-associated proteases in human tissue types. (A) mRNA. (B) Protein. [Data source: Human Protein Atlas (https://www.proteinatlas.org/)].

Figure 4

A schema of virus binding-induced ACE2-mediated dysregulation of RAAS in COVID-19. (SARS-CoV-2 host cell entry receptor ACE2 is an analog of ACE that performs a key step in regulation of RAAS—the conversion of Ang I to Ang II in lung epithelium. Ang II primarily acts through AT1 receptor. Alternatively, Ang II is metabolized to angiotensin 1-7 (Ang 1-7), which further acts through Mas 1R. Physiologically ACE/Ang II/AT1R axis keeps in balance with ACE2/Ang 1-7/Mas 1R axis. Supposedly, binding of SARS-CoV-2 downregulates ACE2 signaling, and consequently ACE/Ang II/AT1R axis gets an upper hand favoring vascular constrictions, tissue inflammation, and fibrosis.) Abbreviations: ACE, angiotensin converting enzyme; Ang I, angiotensin-1; Ang II, angiotensin-2; AT1R, angiotensin 1 receptor; COVID-19, coronavirus disease 2019; Mas 1R, Mas 1 receptor; RAAS, renin–angiotensin–aldosterone system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 5

A schematic description of immune responses in asymptomatic and mildly symptomatic and severe cases of COVID-19. SARS-CoV-2 invasion mediated by host cell entry receptor and entry-associated proteases leads to activation of innate immune response and recruitment of circulating immune cells in lung epithelium. Furthermore, immunological response is varied in asymptomatic/mildly symptomatic and severe cases of COVID-19 patients: (A) asymptomatic and mildly symptomatic cases, an optimum activation of T-cell and humoral-mediated adaptive immune response leads of cure of the patients; (B) in severe cases, a hyperactive innate immune response leading to cytokine storm and consequently killing of T cells and delayed/or suppressed B cell-mediated humoral response resulting in very poor patient outcomes is observed. MIP, macrophage inflammatory protein; MCP, monocyte chemoattractant protein; IL, interleukin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; TNF-α, tissue necrosis factor-α; CCL2, chemokine (C-C motif) ligand 2; CXCL10, chemokine (C-X-C motif) ligand-10; COVID-19, coronavirus disease 2019; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2.

Figure 6

A schema for ACE2-mediated dysfunction of vascular endothelium leading to thrombosis in COVID-19 patients. (Binding of SARS-CoV-2 to ACE2 receptor expressed at the vascular endothelial cell surface leads to internalization and replication of the virus inside the cell and consequently endothelial dysfunction that activates prothrombotic cascade. Additionally, SARS-CoV-2 binding induces downregulation of ACE2, resulting in imbalances of ACE/ACE2 ratio, and dysregulation of RAAS, favoring prothrombosis. Both of these stated mechanisms in consequence also induce activation and aggregation of the platelets, altogether culminating in intravascular thrombosis. Furthermore, NETs that cause increased concentrations of intracellular ROS in neutrophils inducing vascular endothelial dysfunction and activation of coagulation pathways. Furthermore, hypoxia-induced hyperviscosity and upregulation of the HIF-1α signaling pathway can be contributing to the vascular thrombosis.) HIF-1α, hypoxia-inducible factor 1alpha; NETs, neutrophil extracellular traps; ROS, reactive oxygen species; ACE2, angiotensin-converting enzyme-2; TMPRSS2, transmembrane serine protease 2; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; RAAS, renin–angiotensin–aldosterone system.

Figure 7

The spike protein coding sequence mutations in emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants globally. (A) Variants of concern (VOCs). (B) Variants of interest (VOIs). [Analysis included mutations with >75% prevalence in at least one lineage currently recognized by World Health Organization (WHO) as variants of concern and variants of interest globally. Data source: www.outbreak.info, accessed on 28/08/2021].