Metabolic Dysregulation in Severe Malaria

Severe malaria precipitates profound disturbances in host metabolism that contribute to morbidity and mortality. Plasmodium infection can exhaust hepatic stores of glucose, impair adrenal-mediated gluconeogenesis and provoke hypoglycaemia that exacerbates neurological complications. Concurrently, parasite-driven manipulation of lipid pathways induces dyslipidaemia and a lipogenic state in hepatic and adipose tissues, undermining energetic homeostasis. Heightened inflammatory responses further disrupt metabolic signalling, inhibiting insulin sensitivity and altering hormonal axes such as the glucocorticoid response. These perturbations not only compromise organ function but also shape disease tolerance mechanisms, whereby the host must balance pathogen clearance against collateral tissue damage. Understanding the interplay between parasite biology, host hormonal regulation and nutrient metabolism is central to developing interventions that correct metabolic imbalances without necessarily reducing parasite burden.

Research from Nature Portfolio

Investigations into adrenal hormone function have revealed that glucocorticoids play a pivotal role in maintaining glycaemic balance and limiting systemic inflammation during malaria. Removal of adrenal input in murine models led to fatal hypoglycaemia and uncontrolled cerebral cytokine release, whereas synthetic glucocorticoid therapy restored euglycaemia and improved survival. Studies of lipid metabolism have shown that Plasmodium infection down-regulates AMPK phosphorylation in the liver, triggering accumulation of triacylglycerols and free cholesterol. Activation of AMPK by metformin pretreatment prevented lipid build-up and reduced parasite proliferation, illustrating how modulation of host energy sensors can impede parasite development and mitigate tissue damage.

Metabolic Dysregulation in Severe Malaria publication trend

The graph below shows the total number of articles in metabolic dysregulation in severe malaria across all publications each year (not limited to Nature Index journals).

Technical terms

Hypoglycaemia: A pathological drop in blood glucose levels that can lead to neurological dysfunction and increased mortality in severe malaria.

Dyslipidaemia: Abnormal accumulation or distribution of lipids in blood or tissues, often induced by parasite manipulation of host lipid metabolism.

5′ AMP-activated protein kinase (AMPK): A cellular energy sensor that regulates glucose and lipid metabolism; its inhibition by Plasmodium promotes a lipogenic state.

Disease tolerance: Host strategies that minimise tissue damage and maintain function during infection without directly reducing pathogen load.

References

1. Glucocorticoid dysfunction in children with severe malaria. Frontiers in Immunology (2023).
2. Adrenal hormones mediate disease tolerance in malaria. Nature Communications (2018).
3. Plasmodium Infection Induces Dyslipidemia and a Hepatic Lipogenic State in the Host through the Inhibition of the AMPK-ACC Pathway. Scientific Reports (2019).
4. Obesity and Diabetes as Risk Factors for Severe Plasmodium falciparum Malaria: Results From a Swedish Nationwide Study. Clinical Infectious Diseases (2017).
5. Continuous determination of blood glucose in children admitted with malaria in a rural hospital in Mozambique. Malaria Journal (2017).