Impaired ACE2 glycosylation and protease activity lowers COVID‐19 susceptibility in Gitelman's and Bartter's syndromes

COVID 19, Paxlovid and the lesson from rare genetic diseases with naturally occurring protection from SARS-CoV-2 infection

“…This protection has been observed in three surveys repeated in our cohort of Gitelman and Bartter patients carried out during various waves of the pandemic in April 2020, April 2021 and January 2022. These surveys found that none of our 128 patients was hospitalized with COVID-19 and the very few patients who tested positive were either asymptomatic or had very minor symptoms [ 3 , 4 ]. This despite the fact that Gitelman and Bartter syndrome patients have higher ACE2 levels than healthy subjects in addition to renin-angiotensin system activation, yet normo/hypotension and chronic metabolic alkalosis [ 1 , 5 ].…”

“…This despite the fact that Gitelman and Bartter syndrome patients have higher ACE2 levels than healthy subjects in addition to renin-angiotensin system activation, yet normo/hypotension and chronic metabolic alkalosis [ 1 , 5 ]. Chronic metabolic alkalosis in Getelman and Bartter patients could be the basis for the possible presence of a specific intracellular environment not favorable to SARS-CoV-2 infection [ 4 , 6 ].…”

“…In a follow-up study we found that patients with Gitelman and Bartter syndromes have significantly higher non-glycosylated ACE2 levels and lower Cat-L activity compared with healthy individuals [ 4 ]. In addition, their Cat-L activity was inversely correlated to their blood bicarbonate levels [ 4 ].…”

“…In a follow-up study we found that patients with Gitelman and Bartter syndromes have significantly higher non-glycosylated ACE2 levels and lower Cat-L activity compared with healthy individuals [ 4 ]. In addition, their Cat-L activity was inversely correlated to their blood bicarbonate levels [ 4 ]. Thus, alteration of ACE2 glycosylation and Cat-L activity, key elements for virus cell entry and viral replication-transcription, which is likely due to their chronic metabolic alkalosis-dependent alteration of the acidic pH environment in the endosome, provides the rationale for their protection from SARS-CoV-2 infection and/or severe complications [ 4 , 6 ].…”

“…1 A). This is likely the case for the observed protection from SARS-CoV-2 infection in Gitelman and Bartter patients as a result of their chronic metabolic alkalosis via a mutation-driven alteration of the acidic pH of the trans Golgi network/post Golgi pathway in the endosome [ 3 , 4 , 6 ] (Fig. 1 B).I Impaired lysosomal functions, including the alteration of endo-lysomal pH due to lysosomal storage disorders, seem to be the reason for protection from SARS-CoV-2 infection of Fabry disease patients [ 8 ] (Fig.…”