The mucormycete–host interface

Abstract

Mucormycosis is a fungal infection with fulminant angioinvasion leading to high morbidity and mortality in susceptible individuals. The major predisposing conditions are uncontrolled diabetes, neutropenia, malignancies, receipt of a transplant and traumatic injury [1]. Over the past decade, mucormycosis has become an emerging fungal infection due to the increase in patient groups presenting with these pre-disposing conditions and our medical advances in diagnosing the infection [2-4]. Yet, we currently lack clinical interventions to treat mucormycosis effectively. This in turn is due to a lack of understanding of mucormycosis pathogenesis. Here, we discuss our current understanding of selected aspects of interactions at the mucormycete-host interface. We will highlight open questions that might guide future research directions for investigations into the pathogenesis of mucormycosis and potential innovative therapeutic approaches.

Environmental interactions with amoebae as drivers of bacterial-fungal endosymbiosis and pathogenicity

“…Additionally, endobacteria are a source of potent mycotoxins that can influence fungal pathogenesis in plants and insects 59,60,81,90,107,108 . New patient populations are now susceptible to a broadening diversity of basal saprobic fungi, which are a major emerging cause of clinically important superficial and disseminated fungal infections 18,109 . However, the role of endosymbionts in pathogenesis during mammalian mucormycosis has yet to be clinically defined, representing a significant gap in our understanding of the pathogenicity of mucormycetes.…”

“…This is particularly true with Aspergillus fumigatus spores, which mask key cell wall ligands when in a resting state 16,17 . Mucoralean fungi that cause invasive mucormycoses lack many of these strategies, yet remain an important class of fungal pathogens with high mortality in susceptible patient populations 18-20 . Pathogenic Mucorales span multiple genera, with members of the Rhizopus genus most prevalent, causing almost half of all documented cases 21-25 .…”

Recent Advances in the Pathogenesis of Mucormycoses

“…21,22 These cells directly cause damage to and phagocytose both spores and hyphae through the production and release of reactive oxygen metabolites, cationic peptides, perforin, and other antimicrobial enzymes. 13,23 In addition, they produce proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, IFN-γ, and IL-1b, which facilitate activation and recruitment of other immune cells. Any lack or delay in this early inflammatory response can rapidly lead to tissue destruction and disseminated disease.…”

How could hypoglycemia-inducing glycogen storage disease lead to hyperglycemia-induced mucormycosis?

“…One virulence factor of the mucoralean fungi is rapid germination from spores to hyphae. 3 Rapid growth of the hyphae is another virulence factor. Rhizopus species inhibit phagosome maturation in macrophages by the melanin on the spore surface.…”

“…2 Rhizopus species also resist being damaged or killed by decreasing the oxidative burst of phagocytes, which is another virulence factor. 3 Spore coat protein CotH of mucoralean fungi binds to glucose-regulated protein 78 (GRP78) on endothelial cells, promoting angioinvasion, which results in thrombosis and tissue necrosis, yet another virulence factor. 2 The endothelial expression of GRP78 is increased in diabetic ketoacidosis, which brings us to the host factors in mucormycosis.…”