Recent Advances in the Pathogenesis of Mucormycoses
George Petrikkos, MD, PhD ,Constantinos Tsioutis, MD, PhD https://doi.org/10.1016/j.clinthera.2018.03.009

Abstract
Purpose
The purposes of this review are to describe the pathogenesis of mucormycosis and to address recent research advances in understanding the mechanisms of fungal invasion and dissemination.

Methods
Studies and reviews published in the PubMed and ClinicalTrials.gov databases until December 2017 that explored or reported recent advances in the understanding of the pathogenesis of mucormycosis were reviewed.

Findings
To cause disease, fungal spores need to evade the innate immune system and germinate, leading to angioinvasion and tissue destruction. Recent studies have found that Mucorales are able to downregulate several host defense mechanisms and have identified
the specific receptors through which Mucorales attach to the endothelium, facilitating their endocytosis and subsequent angioinvasion. In addition, certain conditions found to act through various mechanisms and pathways in experimental and animal studies,
such as hyperglycemia, elevated iron concentrations, and acidosis (particularly diabetic ketoacidosis), increase the virulence of the fungi and enhance their attachment to the endothelium, rendering patients with uncontrolled diabetes and patients with
iron overload susceptible to mucormycosis. The role and various antifungal functions of platelets and natural killer cells are highlighted, and the potential contribution of alternative therapies, such as manipulating the innate immune host defenses with
granulocyte transfusions or administration of growth factors and using the antifungal effects of calcineurin inhibitors, are presented. Finally, directions and possible implications for future research are provided.

Implications
This article provides a comprehensive overview of research advances in the pathogenesis of infections caused by Mucorales and helps future studies develop effective treatment strategies and improve patient outcomes.

Key words
diabetes; iron; mycormycosis; neutropenia; pathogenesis; Zygomycetes

Address correspondence to: George Petrikkos, MD, PhD, School of Medicine, European University Cyprus, 6 Diogenis str, Engomi, Nicosia, Cyprus.
© 2018 Elsevier Inc. All rights reserved.

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