Mucormycosis is a potentially fatal infection of the sinuses, brain, or lungs, which is most commonly caused by the fungus Rhizopus oryzae. Even if the disease is successfully treated with antifungal agents together with surgery to remove necrotic tissue, survivors are typically left with considerable disfigurement. The condition is seen most often in people with diabetic ketoacidosis (DKA) who have elevated serum glucose and iron levels and a team of researchers at the University of California Los Angeles has now discovered why these individuals are more susceptible to infection. In mucormycosis, fungal invasion of blood vessels results in the formation of blood clots and destruction of local tissue and the team set out to identify the endothelial cell receptor that the fungus uses, and also whether iron and glucose play a role in regulating the expression of the receptor.
In human endothelial cells, glucose-regulated protein 78 (GRP78) was found to play a key role in endocytosis of R. oryzae and subsequent damage; enhanced expression of the protein in the presence of high concentrations of glucose, especially when iron levels are also elevated, offers an explanation of the increased susceptibility of individuals with DKA to mucormycosis. Mice with DKA, which have elevated levels of glucose and available iron, and which are also susceptible to mucormycosis, showed increased expression of GRP78 in sinus, lungs, and brain compared with normal mice. In further studies, treatment of DKA mice with GRP78-specific immune serum was shown to protect them from mucormycosis.
The study, which is published in the Journal of Clinical investigation, provides a new understanding of the pathogenesis of R. oryzae and may lead to new treatments for potentially lethal mucormycosis.