Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages

Abstract

Low oxygen tension is a metabolic hallmark of chronic infection. To investigate the influence of hypoxia on macrophage biology, we analyzed the interaction between the intracellular pathogen Mycobacterium tuberculosis and primary human macrophages. Although the metabolic activity of extracellular M. tuberculosis was reduced at oxygen levels between 0.5 and 10%, the bacilli remained viable throughout the 4 d of culture. Phagocytosis of virulent M. tuberculosis and the pathogen-induced release of inflammatory cytokines by macrophages were not affected by oxygen levels as low as 1%. However, we detected the upregulation of an antimicrobial effector pathway mediated by the vitamin D receptor and human β defensin 2. This finding was functionally relevant, because intracellular mycobacterial growth was inhibited by 58 ± 8% at 1% O2. We conclude that a hypoxic microenvironment, which is characteristic of infected tissue, supports the efficacy of antimicrobial immunity, in part by the upregulation of the antimicrobial peptide human β defensin 2.

Effects of Ascent to High Altitude on Human Antimycobacterial Immunity

“…We have not been able to identify previous human studies of altitude and antimycobacterial immunity. However, our novel finding is supported by experiments in: animals in which altitude augmented antimycobacterial immunity [34]; in cells in which hypoxia stimulated the human vitamin D-dependent antimycobacterial pathway [32]; and in humans whose non-specific cellular immunity was augmented by altitude [35,36]. These findings demonstrate increased immune resistance to mycobacteria at altitude, which offers an explanation for the apparent success of altitude therapy for TB.…”

Inflammation and vitamin D: the infection connection

“…JHR is a cascade of reactions including inflammation, cytokine release, and endotoxin release as part of the immune response to the disintegration of infected cells [172]. This immunopathology suggests transcription of AMPs by an activated VDR, points to the presence of occult infection and provides additional evidence that olmesartan is a VDR agonist [167, 173, 174]. Theoretically, olmesartan restores VDR competence and, thus, phagocytosis leads to bacterial death; consequently, inflammation is temporarily increased by cytokine reaction to microbial endotoxins and cellular debris from dead host cells and bacteria [175].…”

The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition

“…Recent data now show that glycolysis is involved in Mtb growth control in human and murine primary macrophages [87]. A third study also clearly demonstrated significantly decreased growth of Mtb under hypoxia (1% O 2 ), when compared to human macrophages kept at 20% [88]. Importantly, macrophage viability, phagocytosis of live Mtb bacteria and Mtb-induced cytokine release were not affected.…”