[37] Collectively, these studies demonstrate that iron uptake from ferrioxamine is mediated through the reductase/permease system.[37, 38] More recently, we were

able to identify the FOB1 and FOB2 as two closely related genes that encode cell surface proteins involved in binding ferrioxamine to R. oryzae cell surface.[39] Attenuation of expression of these two genes results in compromising the ability of R. oryzae to take up iron from ferrioxamine in vitro and reduces virulence in a deferoxamine-treated mouse model of mucormycosis.[40] A hallmark of mucormycosis is the universal propensity of the infection to invade blood vessels.[1] The Mucorales angioinvasion capabilities likely contribute to the capacity of the organisms to haematogenously disseminate to Selleckchem Olaparib other target organs. Therefore, interactions of invading organisms with endothelial cells and extracellular matrix proteins lining blood vessels represent a critical step in the progression of the disease. Earlier studies demonstrated the ability of Mucorales to bind U0126 in vitro to extracellular

laminin and type IV collagen[41] as well as human umbilical vein endothelial cells.[42] Moreover, Mucorales appear to damage endothelial cells in vitro via a mechanism that involves the induction of their own endocytosis by the mammalian cells.[42] This endocytosis process is mediated by the binding of Mucorales to a mammalian Glucose Regulated Protein with the molecular weight of 78 kDa (GRP78).[43] Interestingly, only germlings of R. oryzae

bind to GRP78 and not spores, thereby fitting the notion that germlings are likely responsible for the haematogenous dissemination Phosphoprotein phosphatase during mucormycosis. Thus far in fungal infection, GRP78 appears to be a unique host cell receptor since neither Candida nor Aspergillus bind to this protein during invasion of host tissues.[43] GRP78 is a heat shock protein that is mainly found in the endoplasmic reticulum acting as a chaperon for facilitating proper protein folding and targeting misfolded proteins for proteosome degradation.[44] It also plays an important role in endoplasmic reticulum Ca2+ homeostasis and in serving as a sensor for stress.[45] Finally, GRP78 was reported to be antiapoptotic and plays critical cytoprotective roles in early embryogenesis, oncogenesis, neurodegenerative diseases and atherosclerosis.[46] Fitting with the concept of GRP78 being a stress-related protein is the finding that GRP78 is overexpressed on the host cell surface when endothelial cells exposed to elevated concentrations of glucose and iron consistent with those seen during hyperglycaemia and DKA. This elevated GRP78 expression results in increased ability of R. oryzae to invade and damage endothelial cells in a receptor-dependent manner.[43] More recently, the Mucorales ligand that binds to GRP78 was identified as the spore coat protein homologs (CotH).