Lysosomal ion channels involved in cellular entry and uncoating of enveloped viruses: Implications for therapeutic strategies against SARS-CoV-2

Zhao, Zhuangzhuang; Qin, Pan; Huang, Yao

doi:10.1016/j.ceca.2021.102360

Cited by 29 publications

(20 citation statements)

References 106 publications

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“…These might include potentially beneficial effects on blood pressure regulation, particularly in older, clinically vulnerable patients who develop a systemic inflammatory response syndrome during the course of the disease, and potentially beneficial effects of calcium channel blockers, which were used as a replacement medication in 52 patients of the discontinuation group. The latter notion is based on evidence that endosomal calcium channels play important roles in cellular entry and uncoating of corona viruses, 32 although evidence for a therapeutic effect of calcium channel blockers in COVID-19 is lacking.…”

Section: Discussionmentioning

confidence: 99%

Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial

Bauer

Schreinlechner

Sappler

et al. 2021

The Lancet Respiratory Medicine

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Background SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin–angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19. Methods ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUC SOFA ), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov , NCT04353596 . Findings Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66–80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00–2·00) vs 1·00 (0·00–3·00); p=0·12). Discontinuation was associated with a significantly lower AUC SOFA (0·00 [0·00–9·25] vs 3·50 [0·00–23·50]; p=0·040), mean SOFA score (0·00 [0·00–0·31] vs 0·12 [0·00–0·78]; p=0·040), and 30-day SOFA score (0·00 [10–90th percentile, 0·00–1·20] vs 0·00 [0·00–24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group. Interpretation Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the avail...

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Section: Discussionmentioning

confidence: 99%

Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial

Bauer

Schreinlechner

Sappler

et al. 2021

The Lancet Respiratory Medicine

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“…From early endosomes, the virus is transported to late endosomes and eventually to lysosomes (Fig 4C ) (Ghosh et al , 2020 ). The internalized virus is uncoated, and the SARS‐CoV‐2 genome is released from the lysosome/late endosome (Fig 4C ) (Bergant Marus\ˇic\ˇ et al , 2012 ; Zhao et al , 2021 ). The viral RNA replicates and is translated to generate the NSPs and structural components of the virus.…”

Section: Resultsmentioning

confidence: 99%

SARS‐CoV‐2–host proteome interactions for antiviral drug discovery

Liu

Huuskonen

Laitinen

et al. 2021

Molecular Systems Biology

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Treatment options for COVID-19, caused by SARS-CoV-2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS-CoV-2-host interactomes and provided great resources for understanding viral replication. However, host proteins that functionally associate with SARS-CoV-2 are localized in the corresponding subnetwork within the comprehensive human interactome. Therefore, constructing a downstream network including all potential viral receptors, host cell proteases, and cofactors is necessary and should be used as an additional criterion for the validation of critical host machineries used for viral processing. This study applied both affinity purification mass spectrometry (AP-MS) and the complementary proximity-based labeling MS method (BioID-MS) on 29 viral ORFs and 18 host proteins with potential roles in viral replication to map the interactions relevant to viral processing. The analysis yields a list of 693 hub proteins sharing interactions with both viral baits and host baits and revealed their biological significance for SARS-CoV-2. Those hub proteins then served as a rational resource for drug repurposing via a virtual screening approach. The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets. Furthermore, antiviral effects of some candidate drugs were observed in vitro validation using image-based drug screen with infectious SARS-CoV-2. In addition, our results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on specific protein-protein interactions.

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“…Cleavage of the viral proteins’ ‘S2′ site’ by cathepsin in the acidic endo-lysosomal compartment then induces fusion of the viral envelope with the late endosome/lysosome membrane to release the viral genome into the cytoplasm [ 152 , 153 , 154 , 155 , 156 ]. This is also referred to as “uncoating” [ 157 , 158 ].…”

Section: Pathophysiology Linked To Ion Channels and Transporters On Lamellar Bodiesmentioning

confidence: 99%

Channels and Transporters of the Pulmonary Lamellar Body in Health and Disease

Dietl

Frick

2021

Cells

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The lamellar body (LB) of the alveolar type II (ATII) cell is a lysosome-related organelle (LRO) that contains surfactant, a complex mix of mainly lipids and specific surfactant proteins. The major function of surfactant in the lung is the reduction of surface tension and stabilization of alveoli during respiration. Its lack or deficiency may cause various forms of respiratory distress syndrome (RDS). Surfactant is also part of the innate immune system in the lung, defending the organism against air-borne pathogens. The limiting (organelle) membrane that encloses the LB contains various transporters that are in part responsible for translocating lipids and other organic material into the LB. On the other hand, this membrane contains ion transporters and channels that maintain a specific internal ion composition including the acidic pH of about 5. Furthermore, P2X4 receptors, ligand gated ion channels of the danger signal ATP, are expressed in the limiting LB membrane. They play a role in boosting surfactant secretion and fluid clearance. In this review, we discuss the functions of these transporting pathways of the LB, including possible roles in disease and as therapeutic targets, including viral infections such as SARS-CoV-2.

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Lysosomal ion channels involved in cellular entry and uncoating of enveloped viruses: Implications for therapeutic strategies against SARS-CoV-2

Cited by 29 publications

References 106 publications

Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial

Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial

SARS‐CoV‐2–host proteome interactions for antiviral drug discovery

Channels and Transporters of the Pulmonary Lamellar Body in Health and Disease

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