Abstract
Mucormycosis is an emerging fungal infection caused by Mucorales with an unacceptable high mortality rate. Mucorales is a complex fungal group, including eleven different genera that can infect humans. This heterogeneity is associated with species-specific invasion pathways and responses to the host defense mechanisms. The host innate immune system plays a major role in preventing Mucorales growth and host invasion. In this system, macrophages are the main immune effector cells in controlling these fungi by rapid and efficient phagocytosis of the spores. However, Mucorales have evolved mechanisms to block phagosomal maturation and species-specific mechanisms to either survive as dormant spores inside the macrophage, as Rhizopus species, or geminate and escape, as Mucor species. Classical fungal models of mucormycosis, mostly Rhizopus, have made important contributions to elucidate key aspects of the interaction between Mucorales and macrophages, but they lack robust tools for genetic manipulation. The recent introduction of the genetically tractable Mucor circinelloides as a model of mucormycosis offers the possibility to analyze gene function. This has allowed the identification of regulatory pathways that control the fungal response to phagocytosis, including a non-canonical RNAi pathway (NCRIP) that regulates the expression of most genes regulated by phagocytosis.
Highlights
Fungal spores are ubiquitous threats to human health that cause diverse pathologies ranging from mild and treatable allergic diseases to lethal infections
All the mucoralean strains causing mucormycosis in humans must be adapted to grow at 37 ◦ C, which means that species isolated from patients that do not belong to the genera Rhizopus and Lichtheimia must present additional molecular adaptations to allow germination inside the phagocytic cells of the host
These molecular adaptations and the mechanisms to overcome the fungicidal attack of macrophages are widely uncharacterized in Mucorales, and their future unveiling will uncover the pathways that different mucoralean species chose to produce mucormycosis
Summary
Fungal spores are ubiquitous threats to human health that cause diverse pathologies ranging from mild and treatable allergic diseases to lethal infections Fungi colonize both indoor and outdoor environments, and their spores pullulate at levels 1000-fold higher than other common airborne allergens [1], making the interaction between fungal pathogens and human hosts virtually inescapable. The lanosterol 14α-demethylase CYP51 F5 presents two amino acid substitutions conserved only in Mucorales, which could explain their intrinsic antifungal resistance to short-tailed azole compounds [7] Another specific feature of Mucorales related to their antifungal resistance is a unique mechanism for the generation of epimutants [8,9]. This review will summarize current information related to macrophage–Mucorales interactions, describing and discussing new advances and future perspectives
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