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Analyzing the Permeability of the Blood-Brain Barrier by Microbial Traversal through Microvascular Endothelial Cells
Published on: February 14, 2020
The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice
Mingfu Liu1, Brad Spellberg, Quynh T Phan
1Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
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.
Insights
Glucose-regulated protein 78 (GRP78) is a novel receptor mediating fungal invasion in mucormycosis. Elevated glucose and iron enhance GRP78 expression, increasing infection risk, particularly in diabetic ketoacidosis (DKA).
Area of Science:
- Mycology
- Infectious Diseases
- Cell Biology
Background:
- Mucormycosis, a severe fungal infection, has a high mortality rate.
- Angioinvasion is a key characteristic of Mucorales infections.
- Patients with elevated serum iron, like those with diabetic ketoacidosis (DKA), are highly susceptible.
Purpose of the Study:
- Identify endothelial cell receptors for Mucorales fungi.
- Investigate the role of iron and glucose in regulating receptor expression.
- Understand the mechanism of host-pathogen interaction in mucormycosis.
Main Methods:
- Identified glucose-regulated protein 78 (GRP78) as a novel host receptor.
- Utilized human endothelial cells and Rhizopus oryzae, Candida albicans, and Aspergillus fumigatus.
- Examined the effects of elevated glucose and iron concentrations on GRP78 expression and fungal invasion.
- Assessed GRP78 expression in DKA mouse models.
- Evaluated the protective effect of GRP78-specific immune serum in DKA mice.
Main Results:
- GRP78 mediates invasion and damage of human endothelial cells by Rhizopus oryzae.
- Elevated glucose and iron enhance GRP78 expression and R. oryzae invasion.
- DKA mice showed increased GRP78 expression in multiple organs.
- GRP78-specific immune serum conferred protection against mucormycosis in DKA mice.
Conclusions:
- GRP78 is a novel host receptor for Rhizopus oryzae, implicated in mucormycosis pathogenesis.
- Increased GRP78 expression due to high glucose and iron contributes to DKA patient susceptibility.
- Targeting GRP78 offers a potential therapeutic strategy for mucormycosis.
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