Hormones in malaria infection: influence on disease severity, host physiology, and therapeutic opportunities

Abstract

Human malaria, caused by Plasmodium parasites, is a fatal disease that disrupts the host's physiological balance and affects the neuroendocrine system. This review explores how malaria influences and is influenced by hormones. Malaria activates the Hypothalamus-Pituitary-Adrenal axis, leading to increased cortisol, aldosterone, and epinephrine. Cortisol, while reducing inflammation, aids parasite survival, whereas epinephrine helps manage hypoglycemia. The Hypothalamus-Pituitary-Gonad and Hypothalamus-Pituitary-Thyroid axes are also impacted, resulting in lower sex and thyroid hormone levels. Malaria disrupts the renin-angiotensin-aldosterone system (RAAS), causing higher angiotensin-II and aldosterone levels, contributing to edema, hyponatremia and hypertension. Malaria-induced anemia is exacerbated by increased hepcidin, which impairs iron absorption, reducing both iron availability for the parasite and red blood cell formation, despite elevated erythropoietin. Hypoglycemia is common due to decreased glucose production and hyperinsulinemia, although some cases show hyperglycemia due to stress hormones and inflammation. Hypocalcemia, and hypophosphatemia are associated with low Vitamin D3 and parathyroid hormone but high calcitonin. Hormones such as DHEA, melatonin, PTH, Vitamin D3, hepcidin, progesterone, and erythropoietin protects against malaria. Furthermore, synthetic analogs, receptor agonists and antagonists or mimics of hormones like DHEA, melatonin, serotonin, PTH, vitamin D3, estrogen, progesterone, angiotensin, and somatostatin are being explored as potential antimalarial treatments or adjunct therapies. Additionally, hormones like leptin and PCT are being studied as probable markers of malaria infection.

Keywords: Human hormones; Plasmodium; antimalarial; host-pathogen interactions; malaria.

Figure 1. Human endocrine organs and the major hormones produced

For hormones, where dysregulation has been reported during malaria has been marked by up (green) and down (red) arrows.

Figure 2. The impact of malaria on Hypothalamus-Pituitary-Adrenal (HPA), Hypothalamus-Pituitary-Thyroid (HPT) and Hypothalamus-Pituitary-Gonad (HPG) axis

Visual representation of the various organs and hormones involved in the (A) HPA, (B) HPT, and (C) HPG hormonal axis. The hormones upregulated during malaria are marked by up arrows; whereas those downregulated are denoted by down arrows. The effect of the hormones on the malaria parasite or pathology are highlighted in the green-outlined boxes.

Figure 3. Diagrammatic overview of the Renin-Angiotensin-Aldosterone System (RAAS) and its role in malaria pathology

The hormones or enzymes upregulated has been denoted by upward arrows. Higher levels of angiotensin-II, leads to vasoconstriction, whereas higher levels of aldosterone and anti-diuretic hormone (ADH) leads to edema and hyponatremia.

Figure 4. Iron regulation and erythropoiesis during malaria

During malaria, Plasmodium infection prompts the liver to increase hepcidin production, reducing iron absorption. Although lower iron levels inhibit parasite growth, they also cause anemia. In response, the kidneys release erythropoietin, stimulating erythropoiesis in the bone marrow and activating erythroblasts to produce erythroferrone. Erythroferrone, in turn, inhibits hepcidin to counteract anemia.