Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

Abstract

The environmental bacterium and potential biothreat agent Burkholderia pseudomallei causes melioidosis, an often fatal infectious disease. Increased serum bilirubin has been shown to be a negative predictive factor in melioidosis patients. We therefore investigated the role of heme oxygenase-1 (HO-1), which catalyzes the degradation of heme into the bilirubin precursor biliverdin, ferrous iron, and CO during B. pseudomallei infection. We found that infection of murine macrophages induces HO-1 expression, involving activation of several protein kinases and the transcription factor nuclear erythroid-related factor 2 (Nrf2). Deficiency of Nrf2 improved B. pseudomallei clearance by macrophages, whereas Nrf2 activation by sulforaphane and tert-butylhydroquinone with subsequent HO-1 induction enhanced intracellular bacterial growth. The HO-1 inducer cobalt protoporphyrin IX diminished proinflammatory cytokine levels, leading to an increased bacterial burden in macrophages. In contrast, HO-1 gene knockdown reduced the survival of intramacrophage B. pseudomallei. Pharmacological administration of cobalt protoporphyrin IX to mice resulted in an enhanced bacterial load in various organs and was associated with higher mortality of intranasally infected mice. The unfavorable outcome of B. pseudomallei infection after HO-1 induction was associated with higher serum IL-6, TNF-α, and MCP-1 levels but decreased secretion of IFN-γ. Finally, we demonstrate that the CO-releasing molecule CORM-2 increases the B. pseudomallei load in macrophages and mice. Thus, our data suggest that the B. pseudomallei–mediated induction of HO-1 and the release of its metabolite CO impair bacterial clearance in macrophages and during murine melioidosis.

Host heme oxygenase‐1: Friend or foe in tackling pathogens?

“…Interestingly, they found that the knockdown of HMOX1 results in clearance of B. pseudomallei, while the treatment of macrophages with an inducer of HMOX1, CoPPIX, leads to an increased bacterial load. In agreement with these findings, the administration of CORM‐2 to mice infected with B. pseudomallei supports higher bacterial growth in the lungs, liver, and spleen .…”

“…Stolt et al,. demonstrated that infection with B. pseudomallei leads to the induction of HMOX1 in RAW264.7 macrophages and murine‐derived primary macrophages . Interestingly, they found that the knockdown of HMOX1 results in clearance of B. pseudomallei, while the treatment of macrophages with an inducer of HMOX1, CoPPIX, leads to an increased bacterial load.…”

Leishmania donovani Exploits Macrophage Heme Oxygenase-1 To Neutralize Oxidative Burst and TLR Signaling–Dependent Host Defense

“…HO-1 is a heme-metabolizing enzyme and plays an important role during oxidant-induced injury (50). The role of HO-1 has been found to be responsible for the successful survival of Mycobacterium abscessus (51) and Burkholderia pseudomallei (52). There are reports that HO-1 also facilitates parasite survival of Leishmania sp.…”

Mycobacterium tuberculosis Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes

“…Heme oxygenase-1 production is induced during the course of several infectious diseases as well as inflammatory disorders and may play beneficial or detrimental role for the host depending on the stimulus and context (29, 30, 40, 51–57). Mtb infection, in particular, induces a robust production of the enzyme detected in plasma (27, 31, 32) suggesting its potential use as a biomarker for TB.…”