2-SARS-CoV-2 and COVID-19.
SARS-CoV-2 enters the cell mainly via the human angiotensin converting
enzyme 2 receptor (hACE2) through glycosylation[9]. In this process,
SARS-CoV-2 is dependent upon plasmatic membrane components as
gangliosides (specially GM-1), that act as attachment cofactors within
lipid raft membrane platforms[9,10]. Dual recognition of both
gangliosides and hACE2 by the spike protein is therefore
needed[9,10]. For this purpose, viral protein displays two distinct
domains: the receptor binding domain that binds to hACE2 receptor and
the N-terminal domain, which binds to the ganglioside-rich domain in the
membrane lipid raft[9,10].
Once this process has been performed, it subsequently penetrates through
endocytosis[11]. Thereafter, lysosomal proteases such as cathepsins,
transmembrane protease TMPRSS2 and furins must activate the fusion
process by cleaving coronavirus surface spike proteins[12–14].
Without endocytosis and lysosome action the replication and infection of
this virus are blocked[12].
In order to facilitate the therapeutic approach of COVID-19, a 3-stage
classification system has been proposed[15]. The first stage is
usually mild with non-specific symptoms and in this phase antiviral
therapy may prevent progression of severity, minimize contagiousness,
and reduce duration of symptoms. In the second stage patients may
develop viral pneumonia 5-7 days after symptoms onset, needing in most
cases hospitalization. The treatment consists of supportive measures and
antiviral therapy. Although most patients are able to clear the
infection in the lung, some will transition into the third and most
severe stage, where the use of immunomodulatory agents may reduce
systemic inflammation. In this phase, patients develop a dysfunctional
immune response leading to a cytokine storm[16]. The development of
such syndrome, characterized by an uncontrolled increase in the
proinflammatory cytokines, has been associated with disease severity and
prognosis[3,16]. This leads to multi-organ damage, including
respiratory failure as a consequence of the development of lung fibrosis
and acute respiratory distress syndrome (ARDS), which is the leading
cause of mortality of this virus[16–18]. In the specific scenario
of ARDS, cytokines may cause epithelial and capillary endothelial
damage[19]. Recently, all these processes have shown to also induce
endotheliitis, which may explain the systemic impaired microcirculatory
function[20].
Azithromycin presents antiviral and immunomodulatory properties that
could be of interest in all these stages, although specific data are
lacking.