Host Immune Defense upon Fungal Infections with Mucorales: Pathogen-Immune Cell Interactions as Drivers of Inflammatory Responses

Abstract

During the last few decades, mucormycosis has emerged as one of the most common fungal infections, following candidiasis and aspergillosis. The fungal order responsible for causing mucormycosis is the Mucorales. The main hallmarks of this infection include the invasion of blood vessels, infarction, thrombosis, and tissue necrosis, which are exhibited at the latest stages of the infection. Therefore, the diagnosis is often delayed, and the rapid progression of the infection severely endangers the life of people suffering from diabetes mellitus, hematological malignancies, or organ transplantation. Given the fact that mortality rates for mucormycosis range from 40 to 80%, early diagnosis and novel therapeutic strategies are urgently needed to battle the infection. However, compared to other fungal infections, little is known about the host immune response against Mucorales and the influence of inflammatory processes on the resolution of the infection. Hence, in this review, we summarized our current understanding of the interplay among pro-inflammatory cytokines, chemokines, and the host-immune cells in response to mucoralean fungi, as well as their potential use for immunotherapies.

Keywords: Lichtheimia; Mucor; Mucoromycotina; Rhizomucor; Rhizopus; epi- and endothelium; innate immune system; macrophages; monocytes; phagocytes; phagocytosis; zygomycosis.

Figure 1

The most common pathogenic mucoralean fungi. Rhizopus oryzae (syn.: Rhizopus arrhizus), Mucor circinelloides, and Lichtheimia corymbifera are the most frequently reported causative agents of mucormycosis. The left panel depicts the colony morphologies of four-week-old R. oryzae and L. corymbifera cultivated on malt extract agar, as well as the colony morphology of one-week-old M. circinelloides cultivated on potato dextrose agar. The right panel represents the corresponding micromorphologies including sporangia (marked with arrows), in which the sporangiospores are produced. Sporangium of R. oryzae presents a dark-brown coloration, while M. circinelloides exhibits a yellow color and L. corymbifera a dark grey pigmentation.

Figure 2

Cytokines and chemokines profiles produced by different host immune cells during mucoralean fungal infection. After recognition of germling and spores of the most common pathogen mucoralean fungi—R. oryzae (syn.: R. arrhizus), M. circinelloides, and L. corymbifera—immune cells produce specific cytokines and chemokines that promote activation and expansion of other immune cells, as well as additional recruitment of leukocytes from the bloodstream to the site of infection. These cytokines regulate the inflammatory response by exerting further pro-inflammatory cascades and promoting communication among the immune cells. As an example, GM-CSF and IFN-γ produced by NK cells and T cells enhance the cytokine production of neutrophils, and their percentages of hyphal damage to R. oryzae, and L. corymbifera. Meanwhile, IL-2 and Il-7 induce the expansion of Mucorales-specific T cells and their production of IL-13, IL-5, TNFα, and IL-10. Moreover, DCs produce IL-23 which promotes the release of IL-17A by T cells.