The Effects of Glucose Metabolism on Cerebral Malaria - Paper Example

Introduction

The article summarized is the “Glucose Metabolism Mediates Disease Tolerance in Cerebral Malaria,” authored by Wang et al. (2018). The article explores how changes in an organism’s metabolic patterns affect its tolerance to an acute inflammatory condition. The inflammatory condition examined, in this case, is cerebral malaria. Cerebral malaria refers to a clinical syndrome whose characteristics involve coma, seizure, and altered consciousness due to Plasmodium falciparum infection (Wang et al., 2018). The condition is very dangerous because it causes more than one million deaths every year despite effective malaria treatment. The mortality rate is high in children below five years. Therefore, there is a need to determine how to improve patients’ tolerance and survival with cerebral malaria. The authors of this article were determined to know the impact of metabolic changes such as anorexia on an organism’s survival with cerebral malaria. Anorexia is a medical condition in which an organism loses its appetite for food. Anorexia denies the body an adequate glucose supply, making it switch to alternative fuels such as ketone bodies and fatty acids (Wang et al., 2018). The main question that the researchers sought to answer with this study was, “… What role does the inhibition of glycolysis using 2-deoxy glucose (2DG) play in the survival and tolerance of patients with cerebral malaria?” It is essential to discuss how the successful completion of this study brought a vital breakthrough to clinical intervention for patients with cerebral malaria.

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Findings and Methods

The following were the key findings obtained from the study. The first finding was that 2-deoxy glucose (2DG) provides significant protection to mice from cerebral malaria. The researchers found out that C57BL/6J male mice infected with Plasmodium berghei ANKA (PbA) developed anorexia (hypophagia) (Wang et al., 2018). The researchers tested the effectiveness of fasting metabolism in enhancing the survival and tolerance of organisms against cerebral malaria. They subjected mice maintained on a ketogenic diet, mice deficient in the fasting hormone Fibroblast Growth Factor 21 (FGF21), and mice deficient in the master regulator of ketogenesis Peroxisome Proliferator-Activated Receptor-α (PPAR-α) to cerebral malaria. The researchers observed no significant difference in the survival of mice deficient in FGF21 and PPAR-α, showing that the components of fasting metabolism increase the survival and tolerance of mice to cerebral malaria (Wang et al., 2018). They confirmed the role of glucose in curtailing cerebral malaria by challenging mice infected with malaria using 2DG and glucose. There were no differences in ketone bodies, plasma-free fatty acids, and glycemia after 2DG or glucose treatment. The study found that glucose did not affect the mortality of mice (Wang et al., 2018). However, 2DG prolonged the survival of mice with cerebral malaria for more than ten days.

The second finding was that 2-deoxy glucose (2DG) has no impact on tissue parasite burden. The first finding that 2DG protected the mice from cerebral malaria triggered the curiosity to determine if it could also affect the tissue parasite burden. Previous studies indicated that Plasmodium depended on the host’s glucose reserves to facilitate its life cycle (Carlos et al., 2018; Vale, 2018). Therefore, it was essential to confirm if 2DG treatment could significantly reduce the tissue parasite load. When researchers subjected the mice to 2DG therapy, there were no observable tissue parasite load differences over time. Besides, the mice with malaria treated with 2DG developed anemia that killed them. The finding confirmed that 2DG does not protect mice from cerebral malaria by the pathogen control mechanism. Therefore, 2DG does not have any impact on tissue parasite load.

The third finding was no impact of 2-deoxy glucose (2DG) treatment on neuroinflammation or cerebral edema. Previous studies found that cerebral malaria disrupts the permeability of the blood-brain barrier (BBB), thereby increasing cerebral edema (Nishanth & Schlüter, 2019; Vale, 2018). Studies have also implicated neuroinflammation as a pathogenesis driver in cerebral malaria, especially for CD8+ T cells (Vale, 2018; Wang et al., 2018). Aerobic glycolysis is required for effector function and cellular activation of leukocytes, including CD8+ T cells (Wang et al., 2018). It was essential to assess if 2DG affects neuroinflammation. By using Evan’s Blue extravasation, researchers found out that 2DG treatment does not affect cerebral edema.

The last finding derived from the study was that 2DG treatment reduced the extent of Stasis-related pathological changes and microthrombi. Cerebral malaria has been associated with hemorrhage disruption of vascular flow, microthrombi, and iRBC sequestration (Wang et al., 2018). Researchers generated brain sections that they treated with vehicle and 2DG to test if 2DG affected vascular events (Wang et al., 2018). They discovered that 2DG treatment reduced hemorrhagic lesions, sequestration, and the number of microthrombi.

Conclusion

Glucose metabolism enhances the survival and tolerance of cerebral malaria in mice. The article provided relevant and timely information that scientists can use to develop reliable solutions to the contemporary threat that cerebral malaria poses. Researchers conducted this study on C57BL/6J male mice infected with Plasmodium berghei ANKA (PbA). The brain structure of mice is clinically similar to human beings. Therefore, this study’s findings are useful for guiding future studies involving tests on humans to determine the reliability and effectiveness of applying glucose metabolism to enhance survival and tolerance of cerebral malaria in human patients.

References

Carlos, A. R., Weis, S., & Soares, M. P. (2018). Cross-talk between iron and glucose metabolism in the establishment of disease tolerance. Frontiers in Immunology, 9, 2498. https://www.frontiersin.org/articles/10.3389/fimmu.2018.02498/full

Nishanth, G., & Schlüter, D. (2019). Blood–brain barrier in cerebral malaria: Pathogenesis and therapeutic intervention. Trends in Parasitology, 35(7), 516-528. https://www.sciencedirect.com/science/article/pii/S1471492219300868

Vale, P. F. (2018). Disease tolerance: Linking sickness behaviors to metabolism helps mitigate malaria. Current Biology, 28(10), R606-R607. https://www.sciencedirect.com/science/article/pii/S0960982218304597

Wang, A., Huen, S. C., Luan, H. H., Baker, K., Rinder, H., Booth, C. J., & Medzhitov, R. (2018). Glucose metabolism mediates disease tolerance in cerebral malaria. Proceedings of the National Academy of Sciences, 115(43), 11042-11047. https://www.pnas.org/content/pnas/115/43/11042.full.pdfAppendix