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.