Indian researchers uncover that G6PD deficiency worsens COVID-19

COVID-19 News: A recent study sheds light on why patients with a common enzymatic deficiency, glucose-6-phosphate dehydrogenase (G6PD), face severe complications when infected with SARS-CoV-2. The research, conducted by teams from Shiv Nadar Institution of Eminence and Jawaharlal Nehru University in India, explores the complex mechanisms behind this vulnerability. This COVID-19 News report delves into the study's key findings and their implications, aiming to present them in a manner accessible to all readers.


Indian researchers uncover that G6PD deficiency worsens COVID-19

G6PD Deficiency and Its Global Impact
Glucose-6-phosphate dehydrogenase (G6PD) is a crucial enzyme in the pentose phosphate pathway, essential for producing NADPH, which protects cells from oxidative damage and supports various cellular functions, including immune responses and biosynthesis of fatty acids and cholesterol.
 
G6PD deficiency, the most prevalent enzymatic disorder globally, affects over 500 million people, with males predominantly affected.
 
This enzyme is vital for the pentose phosphate pathway, which helps cells manage oxidative stress by producing NADPH. A deficiency in G6PD leads to various health issues, including hemolytic anemia, jaundice, increased susceptibility to infections, diabetes, cardiovascular diseases, and neurological disorders. Managing G6PD deficiency involves avoiding triggers such as certain foods (like fava beans) and medications, and regular health monitoring.
 
The study aimed to unpack the science behind this deficiency and its intersection with COVID-19. G6PD's role in cellular health and its impact on the body's ability to fight infections have been well documented.
 
COVID-19 Severity in G6PD Deficient Patients
Clinical observations have shown that patients with G6PD deficiency are more susceptible to severe COVID-19, characterized by prolonged symptoms and higher mortality rates. This vulnerability has puzzled scientists, prompting deeper investigations into the molecular mechanisms at play.
 
The Study and Its Methods
The study utilized CRISPR technology to create a G6PD-deficient human microglia cell model. Microglia are the primary immune cells of the brain, playing a crucial role in the body's defense against pathogens. Researchers focused on these cells to understand how G6PD deficiency affects immune responses, particularly in the context of SARS-CoV-2 infection.
 
Culturing Human Microglia
The research team cultured human microglia cells (HMC3) from ATCC (CRL-3304) in a controlled environment. These cells were maintained in a specific media supplemented with essential nutrients. Experiments were conducted within a range of cell passages to ensure consistency and reliability of results.
 
CRISPR-Mediated G6PD Deficiency
To induce G6PD deficiency, the team employed CRISPR technology. They used a s pecific guide RNA (gRNA) targeting exon-10 of the G6PD gene, a crucial region for the enzyme's function. The edited cells were then selected and expanded for further experiments.
 
Assessing NADPH and Oxidative Stress
The researchers measured NADPH levels and reactive oxygen species (ROS) in both wild-type and G6PD-deficient microglia. They found a significant reduction in NADPH and an increase in basal ROS levels in G6PD-deficient cells. These findings suggest that G6PD deficiency disrupts the cells' ability to manage oxidative stress, a key factor in immune function.
 
Confocal Microscopy and Cellular Co-localization
The team used confocal microscopy to observe the interactions between NO, lysosomes, and viral particles within the cells. They found that NO produced in response to SARS-CoV-2 localized in the lysosomes, where it likely played a role in degrading viral particles. However, in G6PD-deficient cells, this process was significantly impaired.
 
Key Findings and Their Implications
-Reduced NADPH and Increased ROS
NADPH plays a crucial role in regulating oxidative stress. In G6PD-deficient microglia, the researchers observed a dramatic reduction in NADPH levels. This reduction impairs the cells' ability to counteract oxidative stress, leading to higher ROS levels. Elevated ROS can damage cells and tissues, exacerbating inflammatory responses.
 
-Impaired Nitric Oxide Production
Nitric oxide (NO) is a critical molecule in the immune response, particularly in inhibiting viral replication. The study found that G6PD deficiency impairs the production of NO by inducible nitric oxide synthase (iNOS). This impairment reduces the cells' ability to fight off viral infections effectively. The use of a novel in-house probe allowed the researchers to visualize NO production and its localization within the cells, confirming the crucial role of iNOS in this process.
 
-Lysosomal Dysfunction and Viral Clearance
Lysosomes are essential for breaking down and disposing of foreign particles, including viruses. The study revealed that G6PD deficiency affects lysosomal acidification, a process critical for lysosomal function. In G6PD-deficient microglia, lysosomes failed to maintain their acidic environment, impairing their ability to degrade viral particles. This dysfunction may contribute to the increased severity of COVID-19 in G6PD-deficient patients.
 
-Neuroinflammation and SARS-CoV-2
The researchers found that the SARS-CoV-2 spike protein triggers proinflammatory responses in microglia. These responses include the production of cytokines like IL-1β, TNF-α, and IL-12, which play roles in inflammation and immune responses. In G6PD-deficient microglia, however, these proinflammatory signals were less effective, likely due to impaired NO production and lysosomal function.
 
Implications for Treatment
The findings highlight the importance of NADPH in maintaining immune cell function and managing oxidative stress. They suggest potential therapeutic approaches for G6PD-deficient patients, such as NADPH supplementation or NO inhalation therapy, which could support the immune response during infections.
 
Future Research Directions
The study opens avenues for further research into G6PD deficiency and its broader implications. Understanding the genetic and molecular basis of this deficiency can lead to better treatment strategies for affected individuals. Future research should focus on developing therapeutics that enhance NADPH production or mimic its effects, potentially improving outcomes for G6PD-deficient patients.
 
Conclusion
This groundbreaking study from Indian researchers provides valuable insights into the complex interplay between G6PD deficiency and COVID-19 severity. It underscores the critical role of the G6PD-NADPH axis in immune responses and suggests potential therapeutic interventions to improve outcomes for vulnerable patients.
 
The study findings were published in the peer-reviewed journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
https://www.sciencedirect.com/science/article/abs/pii/S092544392400437X
 
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