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The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice
Mingfu Liu, … , Scott G. Filler, Ashraf S. Ibrahim
Mingfu Liu, … , Scott G. Filler, Ashraf S. Ibrahim
Published May 17, 2010
Citation Information: J Clin Invest. 2010;120(6):1914-1924. https://doi.org/10.1172/JCI42164.
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Research Article Infectious disease

The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice

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Abstract

Mucormycosis is a fungal infection of the sinuses, brain, or lungs that causes a mortality rate of at least 50% despite first-line therapy. Because angioinvasion is a hallmark of mucormycosis infections, we sought to define the endothelial cell receptor(s) for fungi of the order Mucorales (the fungi that cause mucormycosis). Furthermore, since patients with elevated available serum iron, including those with diabetic ketoacidosis (DKA), are uniquely susceptible to mucormycosis, we sought to define the role of iron and glucose in regulating the expression of such a receptor. Here, we have identified glucose-regulated protein 78 (GRP78) as what we believe to be a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae, the most common etiologic species of Mucorales, but not Candida albicans or Aspergillus fumigatus. Elevated concentrations of glucose and iron, consistent with those seen during DKA, enhanced GRP78 expression and the resulting R. oryzae invasion and damage of endothelial cells in a receptor-dependent manner. Mice with DKA, which have enhanced susceptibility to mucormycosis, exhibited increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. Finally, GRP78-specific immune serum protected mice with DKA from mucormycosis. These results suggest a unique susceptibility of patients with DKA to mucormycosis and provide a foundation for the development of new therapeutic interventions for these deadly infections.

Authors

Mingfu Liu, Brad Spellberg, Quynh T. Phan, Yue Fu, Yong Fu, Amy S. Lee, John E. Edwards Jr., Scott G. Filler, Ashraf S. Ibrahim

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Figure 4

Downregulation of endothelial cell GRP78 expression with shRNA reduces the number of endocytosed organisms and subsequent damage to endothelial cells.

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Downregulation of endothelial cell GRP78 expression with shRNA reduces t...
Endothelial cells were transduced with lentivirus containing either shRNA targeting GRP78 or a scrambled sequence (Non-target shRNA). Transduction of endothelial cells with GRP78 shRNA lentiviruses reduced GRP78 transcript levels (A), diminished the number of endocytosed R. oryzae germlings (data derived from >800 fungal cells interacting with approximately 250 endothelial cells/each group/experiment, with an average of 76% being endocytosed in the non-target shRNA) (B), and blocked R. oryzae–induced endothelial cell damage (C). *P < 0.005 compared with non-target shRNA by Wilcoxon rank-sum test for all comparisons. n = 6 slides per group from 3 independent experiments for endocytosis, and n = 6 wells per group from 2 independent experiments for damage assay. Data are expressed as median ± interquartile range.

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