Abstract
Mucormycosis is a life-threatening fungal infection caused by various ubiquitous filamentous fungi of the Mucorales order, although Rhizopus spp. and Mucor spp. are the most prevalent causal agents. The limited therapeutic options available together with a rapid progression of the infection and a difficult early diagnosis produce high mortality. Here, we developed an adult zebrafish model of Mucor circinelloides infection which allowed us to confirm the link between sporangiospore size and virulence. Transcriptomic studies revealed a local, strong inflammatory response of the host elicited after sporangiospore germination and mycelial tissue invasion, while avirulent and UV-killed sporangiospores failed to induce inflammation and were rapidly cleared. Of the 857 genes modulated by the infection, those encoding cytokines, complement factors, peptidoglycan recognition proteins, and iron acquisition are particularly interesting. Furthermore, neutrophils and macrophages were similarly recruited independently of sporangiospore virulence and viability, which results in a robust depletion of both cell types in the hematopoietic compartment. Strikingly, our model also reveals for the first time the ability of mucormycosis to induce the apoptosis of recruited macrophages but not neutrophils. The induction of macrophage apoptosis, therefore, might represent a key virulence mechanism of these fungal pathogens, providing novel targets for therapeutic intervention in this lethal infection.
Highlights
Mucormycosis is a life-threatening fungal infection caused by various ubiquitous filamentous fungi of the Mucorales order, Rhizopus spp. and Mucor spp. are the most prevalent causal agents[1]
A phylogenetic analysis based on multi-locus sequence typing established three different M. circinelloides subspecies corresponding to the M. circinelloides f. lusitanicus (Mcl), M. circinelloides f. griseocyanus (Mcg), and M. circinelloides f. circinelloides (Mcc)
The results showed that 2.5 × 105 sporangiospores consistently resulted in 100% mortality of zebrafish infected with R7B as early as 24 hpi and no mortality with the same dose of NRRL sporangiospores (Fig. 1A)
Summary
Mucormycosis is a life-threatening fungal infection caused by various ubiquitous filamentous fungi of the Mucorales order, Rhizopus spp. and Mucor spp. are the most prevalent causal agents[1]. A zebrafish larval infection model has been recently established to study early innate immune response to M. circinelloides in a whole-animal system and in real-time in vivo[12] Despite that this model has been used with an Mcl strain, which is avirulent in a diabetic murine model and shows reduced virulence in wax moth host, it mimics a range of aspects of human mucormycosis showing that macrophages and neutrophils were readily recruited to the site of infection. Our results confirm the link between sporangiospore size and virulence previously in wax moth[9], larval zebrafish[12] and murine[14] models, but reveal a robust inflammatory response elicited after sporangiospore germination and mycelial tissue invasion This host inflammatory response is characterized by neutrophil and macrophages mobilization from the kidney, the main adult fish hematopoietic organ, to the infection site, and the modulation of 857 genes related to immune response and iron metabolism, among others. The results uncover a previously unappreciated ability of mucormycosis to induce the apoptosis of recruited macrophages, what might represent a key virulence mechanism of this fungal infection providing a novel target for therapeutic intervention
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