Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

Logo MUG-Forschungsportal

Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Schmidt, IHE; Gildhorn, C; Böning, MAL; Kulow, VA; Steinmetz, I; Bast, A.
Burkholderia pseudomallei modulates host iron homeostasis to facilitate iron availability and intracellular survival.
PLoS Negl Trop Dis. 2018; 12(1):e0006096-e0006096 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Steinmetz Ivo
Altmetrics:

Dimensions Citations:

Plum Analytics:
Number of Figures: 8
| | | | | | | |
Abstract:
The control over iron homeostasis is critical in host-pathogen-interaction. Iron plays not only multiple roles for bacterial growth and pathogenicity, but also for modulation of innate immune responses. Hepcidin is a key regulator of host iron metabolism triggering degradation of the iron exporter ferroportin. Although iron overload in humans is known to increase susceptibility to Burkholderia pseudomallei, it is unclear how the pathogen competes with the host for the metal during infection. This study aimed to investigate whether B. pseudomallei, the causative agent of melioidosis, modulates iron balance and how regulation of host cell iron content affects intracellular bacterial proliferation. Upon infection of primary macrophages with B. pseudomallei, expression of ferroportin was downregulated resulting in higher iron availability within macrophages. Exogenous modification of iron export function by hepcidin or iron supplementation by ferric ammonium citrate led to increased intracellular iron pool stimulating B. pseudomallei growth, whereas the iron chelator deferoxamine reduced bacterial survival. Iron-loaded macrophages exhibited a lower expression of NADPH oxidase, iNOS, lipocalin 2, cytokines and activation of caspase-1. Infection of mice with the pathogen caused a diminished hepatic ferroportin expression, higher iron retention in the liver and lower iron levels in the serum (hypoferremia). In vivo administration of ferric ammonium citrate tended to promote the bacterial growth and inflammatory response, whereas limitation of iron availability significantly ameliorated bacterial clearance, attenuated serum cytokine levels and improved survival of infected mice. Our data indicate that modulation of the cellular iron balance is likely to be a strategy of B. pseudomallei to improve iron acquisition and to restrict antibacterial immune effector mechanisms and thereby to promote its intracellular growth. Moreover, we provide evidence that changes in host iron homeostasis can influence susceptibility to melioidosis, and suggest that iron chelating drugs might be an additional therapeutic option.

© Meduni Graz Impressum