Hypoxia-Inducible Factor-1 Alpha Stabilization in Human Macrophages during Leishmania major Infection Is Impaired by Parasite Virulence

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is one of the master regulators of immune and metabolic cellular functions. HIF-1 alpha, a transcriptional factor whose activity is closely related to oxygen levels, is a target for understanding infectious disease control. Several studies have demonstrated that HIF-1 alpha plays an important role during the infectious process, while its role in relation to parasite virulence has not been addressed. In this work, we studied the expression levels of HIF-1 alpha and related angiogenic vascular endothelial growth factor A (VEGF-A) in human macrophages infected with promastigotes of hypo- or hyper-virulent Leishmania major human isolates. L. major parasites readily subverted host macrophage functions for their survival and induced local oxygen consumption at the site of infection. In contrast to hypo-virulent parasites that induce high HIF-1 alpha expression levels, hyper-virulent L. major reduced HIF-1 alpha expression in macrophages under normoxic or hypoxic conditions, and consequently impeded the expression of VEGF-A mRNA. HIF1a may play a key role during control of disease chronicity, severity, or outcome.

Automated summary

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a master regulator of immune and metabolic cellular functions. In this study, it was found that high-virulent Leishmania major reduces the expression levels of HIF-1 alpha in macrophages, thereby inhibiting the expression of related genes.