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.