Potential resistance to SARS-CoV-2 infection in lysosomal storage disorders

On 11 March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) outbreak to be a ‘pan- demic’. In the following months, the disease spread in Italy to include >2 million infected patients (3.7% of the population), with >80 000 COVID-19-related deaths. While vaccines have been developed, based on the current knowledge of biology of coronavirus infection, COVID-19 is empirically treated with antivirals, immunomodulatory and antimalarial drugs, but most of these approaches do not specifically target the cellular mechanisms involved in viral entry and spreading. It has been demonstrated that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human and some animal cell lines through the Angiotensin-converting enzyme 2 (ACE2) receptor, but the endocytic pathway represents an alter- native entry route for SARS-CoV-2 and other several viruses, including Ebola virus and African swine fever virus. The endo- somal protein, Niemann–Pick C1, deficiency in which causes the lysosomal disorder Niemann–Pick disease type C (NPC) , has been identified as a necessary entry receptor for Ebola virus [1, 2]. Similarly, it is well established that SARS-CoV-2 infection requires an acidic endosomal environment [3]. Of note, endo- some luminal pH and further vesicle maturation are controlled by ion channels, pumps and membrane proteins, suggesting that drugs targeting these structures may potentially have broad-spectrum antiviral properties. Indeed, recent studies have described the inhibitory effect of experimental and Food and Drug Administration-approved drugs acting on the endoso- mal compartment against viruses of high relevance for human and animal health, including SARS-CoV-2 and Ebola virus (Figure 1A) [4]. In Fabry disease, the genetically determined deficit of alpha- galactosidase A leads to glycosphingolipids accumulation in kidney, heart, vessels and lungs. Glycosphingolipid storage causes impairment of several lysosomal