Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an enveloped, single-stranded RNA virus. Humans infected with SARS-CoV-2 develop a disease known as coronavirus disease 2019 (COVID-19) with symptoms and consequences including acute respiratory distress syndrome (ARDS), cardiovascular disorders, and death. SARS-CoV-2 appears to infect cells by first binding viral spike proteins with host protein angiotensin-converting enzyme 2 (ACE2) receptors; the virus is endocytosed following priming by transmembrane protease serine 2 (TMPRSS2). The process of virus entry into endosomes and its release from endolysosomes are key features of enveloped viruses. Thus, it is important to focus attention on the role of endolysosomes in SARS-CoV-2 infection. Indeed, coronaviruses are now known to hijack endocytic machinery to enter cells such that they can deliver their genome at replication sites without initiating host detection and immunological responses. Hence, endolysosomes might be good targets for developing therapeutic strategies against coronaviruses. Here, we focus attention on the involvement of endolysosomes in SARS-CoV-2 infection and COVID-19 pathogenesis. Further, we explore endolysosome-based therapeutic strategies to restrict SARS-CoV-2 infection and COVID-19 pathogenesis.

Curcumin as a Potential Treatment for COVID-19

“…The entry of SARS-CoV-2 through the endosome requires an endosomal environment with an acidic pH that is promoted by the endosomal proteases, cathepsin B and L, and ion channels, particularly the vacuolar ATPase pump (V-ATPase), which is crucial in regulating endosomal pH (Aslam and Ladilov, 2020;Khan et al, 2020). Curcumin has been shown to be a potential pH controlling agent, decreasing the expression of V-ATPase, which causes an increase in pH in tumor cells (Vishvakarma et al, 2011).…”

Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease

“…Expression level of these proteases depends on cell type and hence their relative importance to support successful infection would hinge in part on their relative expression. Cathepsin is primarily found in late endosomes or lysosomes and requires low pH for optimal enzymatic activity; for these reasons it has been proposed that SARS-CoV-2 entry occurs from the endolysosomal compartment (32, 33). In contrast, TMPRSS2 is thought to be at the cell surface (34) and its optimal proteolytic activity is pH independent (35); hence it has been inferred that TMPRSS2 cleavage of spike S protein occurs on virions at the plasma membrane from which viral entry is then assumed to occur (1).…”

Vitamin D status of Arab Gulf residents screened for SARS-CoV-2 and its association with COVID-19 infection: a multi-centre case–control study

“…This inhibitory relationship between VDR and STAT1 suggests that unbinding of the latter through stimulation with biologically active forms of vitamin D (calcitriol) strengthens type 1 IFN response, which, in turn, improves innate immune system [ 34 ]. Another mechanism by which 25(OH)D can promote coronavirus degradation is through autophagy via acidification of endolysosomes, cellular organelles responsible for the release of SARS-CoV-2 in the cytosol [ 35 , 36 ]. Lastly, it is now known that COVID-19 downregulates the expression of ACE2 receptors, and there is evidence that vitamin D upregulates ACE2, which can bind to SARS-CoV-2 and prevent it from binding to ACE2 receptor [ 37 – 39 ].…”