Host cell invasion in mucormycosis: role of iron

Abstract

Clinical hallmarks of mucormycosis infections include the unique susceptibility of patients with increased available serum iron, the propensity of the organism to invade blood vessels, and defective phagocytic function. These hallmarks underscore the crucial roles of iron metabolism, phagocyte function, and interactions with endothelial cells lining blood vessels, in the organism's virulence strategy. In an attempt to understand how Mucorales invade the host, we will review the current knowledge about interactions between Mucorales and the host while evading phagocyte-mediated killing. Additionally, since iron is an important determinant of the disease, we will focus on the role of iron on these interactions. Ultimately, a superior understanding of the pathogenesis of mucormycosis will enable development of novel therapies for this disease.

Figure 1

Increasing incidence of mucormycosis at a tertiary care center compiled from Chakrabarti et al. 2008 and 2009.[9,10]

Figure 2

Proposed mechanisms of host invasion by Mucorales during mucormycosis. Mucormycosis is contracted through inhalation, ingestion, or direct inoculation into an abraded skin of Mucorales spores. These spores enter tissues by binding to exposed extracellular matrix proteins due to epithelial cell damage in a susceptible host. It is also possible that Mucorales first invade epithelial cells then penetrate the extracellular matrix protein via the action of secreted proteases. Once inside the tissues and due to immunosuppressive predisposing factors, Mucorales evade tissue macrophage (MØ)-mediated killing and invade blood vessels by binding to extracellular matrix proteins followed by invading endothelial cells. In a susceptible host, Mucorales thrive in an invaded blood vessel due to the abundance of free iron (e.g. release of iron from transferrin (T) via a proton-mediated mechanism in DKA patients) and the lack of or the presence of ineffective PMNL. Germlings adhere to endothelial cell through a receptor that is yet to be determined. Next, Mucorales invade endothelial cells by binding to GRP78 which is overexpressed and re-localized to the endothelial cell surface in high concentrations of glucose and iron often seen in DKA patients. Finally, fungal hyphae penetrate the blood vessel and seed target organs.