The story behind the virus with the crown
Coronaviruses belong to a large group of related viruses, named coronavirus family, which can infect humans and animals and lead to diseases of the airways, the gut, liver, and the nervous system. Some members of coronavirus family may infect the upper airways with rather mild courses and others - as severe acute respiratory syndrome coronavirus SARS-CoV-2 – may affect the lower respiratory airways with pneumonia and fatal courses (Table 1) (1, 2 ).
Belonging to the β-Coronavirus genus, SARS-CoV-2 is the pathogen that causes the new infectious respiratory disease, termed as coronavirus disease 19 (COVID-19), which emerged in December 2019, in Wuhan (Hubei province, China) first and later turned to be a global pandemic (2 ). SARS-CoV-2 displays 79% nucleotide identity with SARS-CoV and 51.8% nucleotide identity with MERS-CoV, but most importantly shares 96% identity across the entire genome with a bat coronavirus, which is supposed to be the natural origin of SARS-CoV-2 (1, 3, 4 ).
As other coronaviruses, SARS-CoV-2 is an enveloped, positive-sense single-stranded RNA virus with spikes that protrude from the virus surface resembling a crown or “corona” (Fig. 1). Most importantly, the spike (S) protein of coronaviruses is essential for viral infection of host cells. During the virus entry procedure, the S protein engages its cellular receptor, angiotensin-converting enzyme 2 (ACE2), which facilitates viral attachment to the cell surface of target cells. As a next step, the engaged S protein is further primed by the cellular serine protease (Transmembrane Protease Serine 2) TMPRSS2, which mediates membrane fusion and viral entry into the cells (Fig. 1) (5, 6 ). Importantly, as the efficiency of ACE2-S interaction largely determines SARS-CoV transmissibility (7-9 ), the expression of ACE2 receptors represents a major risk factor for the vulnerability to SARS-CoV-2 infection. In humans, the ACE2 receptors are expressed by CD8+ T cells (10 ), resting and activated natural killer (NK) cells (10 ), alveolar epithelial cells of type II (11 ), vascular endothelial cells, macrophages and adipocytes (12 ). The nose and the nasal epithelium plays an important role for infection and viral spreading (13, 14 ). High ACE2 expression has also been demonstrated on epithelial cells of the oral mucosa, in particular the tongue, so that this receptor might provide an entry route for the virus and designates the oral cavity as a potential organ at high risk for viral spreading from one individual to the other (15 ). Tissue distribution of the ACE2 gene includes the small intestine, testis, kidneys, heart, thyroid, and adipose tissue with relatively high expression (12 ). It has been recently demonstrated that the inflammatory cytokines interferon (IFN)-α2 and IFN-γ increase the expression of ACE2 and is supposed that tissue inflammation may modulate the receptor expression and thereby change the risk of immune cells to be infected by SARS-CoV-2 (14 ). So far, a positive correlation of ACE2 gene expression to CD8+ cells in the skin has been shown12 ).
Binding of SARS-CoV-2 to ACE2 downregulates its expression and impacts thereby on its main function, the regulation of the renin-angiotensin system. This downregulation leads to a dysregulation of the balance of soluble factors, electrolytes, blood pressure combined with an increase of vascular permeability and lung inflammation (1 ). Usually, virus-specific T cells recruited to the site of inflammation eliminate the virus with neutralizing antibodies generated from B cells and macrophages and prevent thereby virus spreading in an immunocompetent individual (1, 16 ). However, inflammation-induced cell death of infected cells and damage-released molecular patterns might induce proinflammatory cytokines and chemokines and recruitment of inflammatory cells to the lung (Fig. 2). Thus, the lung tissue damage caused by SARS-CoV-2 infection and replication, may thereby destroy step-wise the lung structure with the development of pulmonary fibrosis by transformation of adipocytes into myofibroblasts (17 ). The knowledge accumulated from SARS and MERS, together with current clinical observations from COVID-19 patients, suggest that type-I IFN-mediated antiviral responses and activation of both CD4+ Th1 and CD8+ cytotoxic T lymphocytes (CTLs) result in viral clearance in SARS-CoV-2 infected subjects with mild symptoms. However, insufficient initiation of antiviral immune responses, increased production of inflammatory cytokines, as well as lung infiltration of monocytes and neutrophils, contribute to a cytokine storm in SARS-CoV-2 positive patients (18, 19 ). Moreover, the cytokine storm elicited from the overproduction of pro-inflammatory mediators such as interleukin (IL)-1, IL-6, IL-12, and tumor necrosis factor (TNF)-α, not only leads to increased vascular permeability and inflammation in the lung (18, 19 ) but may reach other organs through the vascular system. In the worst case, this might induce injury of multiple other organs including the cardiac, renal or hepatic system (Fig. 2) (1 ). This cascade of events might lead despite intensive care and a lot of other measures initiated, to fatal courses and death, in particular in elderly patients and individuals with pre-existing diseases.