1. G6PD deficiency mediated impairment of iNOS and lysosomal acidification affecting phagocytotic clearance in microglia in response to SARS-CoV-2.
- Author
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Mondal A, Munan S, Saxena I, Mukherjee S, Upadhyay P, Gupta N, Dar W, Samanta A, Singh S, and Pati S
- Subjects
- Humans, Glucosephosphate Dehydrogenase metabolism, Glucosephosphate Dehydrogenase genetics, NADP metabolism, Nitric Oxide metabolism, Oxidative Stress, Reactive Oxygen Species metabolism, Cells, Cultured, COVID-19 metabolism, COVID-19 pathology, COVID-19 virology, COVID-19 immunology, Glucosephosphate Dehydrogenase Deficiency metabolism, Glucosephosphate Dehydrogenase Deficiency pathology, Glucosephosphate Dehydrogenase Deficiency genetics, Lysosomes metabolism, Microglia metabolism, Microglia pathology, Nitric Oxide Synthase Type II metabolism, Nitric Oxide Synthase Type II genetics, Phagocytosis
- Abstract
The glucose-6-phosphate dehydrogenase (G6PD) deficiency is X-linked and is the most common enzymatic deficiency disorder globally. It is a crucial enzyme for the pentose phosphate pathway and produces NADPH, which plays a vital role in regulating the oxidative stress of many cell types. The deficiency of G6PD primarily causes hemolytic anemia under oxidative stress triggered by food, drugs, or infection. G6PD-deficient patients infected with SARS-CoV-2 showed an increase in hemolysis and thrombosis. Patients also exhibited prolonged COVID-19 symptoms, ventilation support, neurological impacts, and high mortality. However, the mechanism of COVID-19 severity in G6PD deficient patients and its neurological manifestation is still ambiguous. Here, using a CRISPR-edited G6PD deficient human microglia cell culture model, we observed a significant reduction in NADPH level and an increase in basal reactive oxygen species (ROS) in microglia. Interestingly, the deficiency of the G6PD-NAPDH axis impairs induced nitric oxide synthase (iNOS) mediated nitric oxide (NO) production, which plays a fundamental role in inhibiting viral replication. Surprisingly, we also observed that the deficiency of the G6PD-NADPH axis reduced lysosomal acidification and free radical production, further abrogating the lysosomal clearance of viral particles. Thus, impairment of NO production, lysosomal functions, and redox dysregulation in G6PD deficient microglia altered innate immune response, promoting the severity of SARS-CoV-2 pathogenesis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
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