Mucorales Species and Macrophages

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.

Keywords: RNAi; apoptosis; germination; iron; melanin; nutritional immunity; phagosome maturation.

Figure 1

Mechanisms of Mucor circinelloides to escape from macrophage fungistatic activity. When M. circinelloides spores are phagocytized, a complex gene response is activated to survive macrophages attack that encompasses the differential expression of genes involved in defense mechanisms, extracellular structures, metabolism, and cell wall [57]. This response also up-regulates transcription factors atf1 and atf2 that regulate germination at low pH and other processes involved in the response to phagocytosis [57]. Calcineurin pathway is also activated and promotes phagosome maturation arrest [63]. The spore response to phagocytosis also comprises the activation of macrophage genes involved in apoptosis and proinflammatory response [57]. The NCRIP represses most of the genes of the phagocytosis-activated response in the absence of macrophages [58], suggesting that some of the signals present in the phagosome repress this RNAi-related pathway to allow the activation of the spore response to phagocytosis. Green arrow, activation; red T, repression.