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

Abstract

Hypoxia-inducible factor-1 alpha (HIF-1α) is one of the master regulators of immune and metabolic cellular functions. HIF-1α, 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-1α 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-1α and related angiogenic vascular endothelial growth factor A (VEGF-A) in human macrophages infected with promastigotes of hypo- or hyper-virulent <i>Leishmania major</i> human isolates. <i>L. major</i> 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-1α expression levels, hyper-virulent <i>L. major</i> reduced HIF-1α expression in macrophages under normoxic or hypoxic conditions, and consequently impeded the expression of VEGF-A mRNA. HIF-1α may play a key role during control of disease chronicity, severity, or outcome.

Regulatory Functions of Hypoxia in Host–Parasite Interactions: A Focus on Enteric, Tissue, and Blood Protozoa

“…may elicit different hypoxic responses [ 135 ]. Finally, hyper-virulent Leishmania strains reduced HIF-1α expression, whereas hypo-virulent strains increased HIF-1α expression, indicating different strains within the same species can also elicit different hypoxic responses that may contribute to or mitigate virulence [ 136 ].…”

mTOR signaling pathway regulation HIF-1 α effects on LPS induced intestinal mucosal epithelial model damage

“…In sepsis, during the inflammatory process, tissue metabolism is high, oxygen consumption increases, intestinal mucosal vessels constrict, mucosal permeability increases [ 6 ], oxygen supply decreases, and the degree of hypoxia in intestinal epithelial cells increases [ 7 ]. Hypoxia-inducible factor−1 is a key transcription factor required for the human body to adapt to hypoxic environments and plays an important role in the development of sepsis [ 8 ].…”