Pathogenesis of mucormycosis

Abstract

Mucormycosis is a life-threatening infection that occurs in patients who are immunocompromised because of diabetic ketoacidosis, neutropenia, organ transplantation, and/or increased serum levels of available iron. Because of the increasing prevalence of diabetes mellitus, cancer, and organ transplantation, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy, which includes disfiguring surgical debridement and frequently adjunctive toxic antifungal therapy, the overall mortality rate is high. New strategies to prevent and treat mucormycosis are urgently needed. Understanding the pathogenesis of mucormycosis and the host response to invading hyphae ultimately will provide targets for novel therapeutic interventions. In this supplement, we review the current knowledge about the virulence traits used by the most common etiologic agent of mucormycosis, Rhizopus oryzae. Because patients with elevated serum levels of available iron are uniquely susceptible to mucormycosis and these infections are highly angioinvasive, emphasis is placed on the ability of the organism to acquire iron from the host and on its interactions with endothelial cells lining blood vessels. Several promising therapeutic strategies in preclinical stages are identified.

Figure 1.

Proposed mechanisms of iron uptake by Mucorales during mucormycosis. A, Because of the angioinvasive nature of the disease, heme (H) is likely to represent a source of iron to the invading fungus, which either takes up heme intracellularly or strips ferric iron from heme by the action of the reductase-permease system. If heme is transported intracellulary, ferric iron is obtained by the action of heme oxygenase in the cytoplasm. B, In patients with DKA, proton (H⁺)–mediated displacement of ferric iron (Fe³⁺) from transferrin (T) increases the availability of iron, which is transported intracellularly by the reductase-permease system. C, Deferoxamine (D) directly chelates iron from transferrin, resulting in ferrioxamine (iron-deferoxamine complex). The fungus then liberates ferrous iron from ferrioxamine by reduction at the cell surface. In all cases, iron is transported across the cell membrane by the copper oxidase–iron permease (FTR1) complex.