Figure 3 - uploaded by Mohamed Abdelwahab Hassan
Content may be subject to copyright.
Evolution of 27 human pathogenic species within the order Mucorales based on Bayesian inferred phylogenetic analysis of four-locus phylogeny comprising 807 and 1,092 characters of exonic genes from actin and translation elongation factor EF1 alpha as well as 1215 and 389 characters of the nuclear small (18S) and the large (28S) subunit rRNA, respectively. Clade stability values obtained by Bayesian, distance and Maximum Parsimony analysis, are given above the branches with the following meaning: Full black dots: Clade support equal or greater than 95%; White dots: Clade support equal or greater than 90%; #: Clade support equal or greater than 75%; +: Clade support equal or greater than 95% but only in Bayesian analysis; $: Clade support equal or greater than 75%, but only in Bayesian and Neighbor-Joining analysis. The tree is rooted in three species of the Mortierellales including the animal pathogenic Mortierella wolfii used as an outgroup. The family structure is indicated in accordance with Voigt et al. (2009) 119 and Hoffmann et al. (2012). 120 -Adopted from Voigt (2012, 138-139). 121 The pathogenic potential of the species was evaluated based on Hoog et al. (2009). 18 This Figure is reproduced in color in the online version of Medical Mycology.
Source publication
Fungi of the basal lineage order Mucorales are able to cause infections in animals and humans. Mucormy-
cosis is a well-known, life-threatening disease especially in patients with a compromised immune system.
The rate of mortality and morbidity caused by mucormycosis has increased rapidly during the last decades,
especially in developing countries....
Similar publications
Mucormycosis has emerged as a group of severe infections mainly in immunocompromised patients. We analysed the epidemiology of mucormycosis in Greece in a multicentre, nationwide prospective survey of patients of all ages, during 2005–2022. A total of 108 cases were recorded. The annual incidence declined after 2009 and appeared stable thereafter,...
Citations
... Mucormycosis, a severe fungal infection caused by Mucorales fungi, aggressively invades human blood, organs, and tissues. It poses a significant threat to children with suppressed immune function post-transplantation, with a high mortality rate (Cornely et al., 2019;Hassan and Voigt, 2019). Recent epidemiologic research reveals that mucormycosis is the third most prevalent invasive fungal disease among children trailing behind aspergillosis and candidiasis (Francis et al., 2018). ...
... Recent epidemiologic research reveals that mucormycosis is the third most prevalent invasive fungal disease among children trailing behind aspergillosis and candidiasis (Francis et al., 2018). There has been a notable increase in mucormycosis cases over recent years (Bitar et al., 2014), with rates in Asia ranging from 1 to 12.3 per million (Hassan and Voigt, 2019).The condition predominantly impacts individuals with diabetes or compromised immunity, including those with hematologic malignancies, transplant recipients, and patients who have undergone surgery, experienced burns, or suffered trauma (Feng and Sun, 2018). ...
Background
Mucormycosis is an uncommon invasive fungal infection that has a high mortality rate in patients with severe underlying diseases, which leads to immunosuppression. Due to its rarity, determining the incidence and optimal treatment methods for mucormycosis in children is challenging. Metagenomic next-generation sequencing (mNGS) is a rapid, precise and sensitive method for pathogen detection, which helps in the early diagnosis and intervention of mucormycosis in children. In order to increase pediatricians’ understanding of this disease, we conducted a study on the clinical features of mucormycosis in children and assessed the role of mNGS in its diagnosis.
Methods
We retrospectively summarized the clinical data of 14 children with mucormycosis treated at the First Affiliated Hospital of Zhengzhou University from January 2020 to September 2023.
Results
Of the 14 cases, 11 case of mucormycosis were classified as probable, and 3 cases were proven as mucormycosis. Most children (85.71%) had high-risk factors for mucormycosis. All 14 children had lung involvement, with 5 cases of extrapulmonary dissemination. Among the 14 cases, 4 cases underwent histopathological examination of mediastinum, lung tissue or kidney tissue, in which fungal pathogens were identified in 3 patients. Fungal hyphae was identified in 3 cases of mucormycosis, but only 1 case yielded a positive culture result. All patients underwent mNGS testing with samples from blood (8/14), bronchoalveolar lavage fluid (6/14), and tissue (1/14). mNGS detected fungi in all cases: 7 cases had Rhizomucor pusillus, 4 cases had Rhizopus oryzae, 3 cases had Rhizopus microsporus, 1 case had Lichtheimia ramosa, and 1 case had Rhizomucor miehei. Coinfections were found with Aspergillus in 3 cases, bacteria in 3 cases, and viruses in 5 cases.
Conclusion
Children with mucormycosis commonly exhibit non-specific symptoms like fever and cough during the initial stages. Early diagnosis based on clinical symptoms and imaging is crucial in children suspected of having mucormycosis. mNGS, as a supplementary diagnostic method, offers greater sensitivity and shorter detection time compared to traditional mucormycosis culture or histopathological testing. Additionally, mNGS enables simultaneous detection of bacteria and viruses, facilitating timely and appropriate administration of antibiotics and thereby enhancing patient outcomes.
... Considering that fungi of the order Mucorales are commonly associated to opportunistic infections [17,18], ensuring their safety for animals is a mandatory step while designing a parasite biocontrol program, namely through anatomopathological, cytotoxicity, hematological and fecal analysis. In fact, all previous studies revealed that parasitized animals receiving M. circinelloides spores maintained or even improved the hematological parameters and feces consistency and appearance, and also without damaging the internal tissues [19][20][21][22]. ...
Background
The combined application of predatory fungi and antiparasitic drugs is a sustainable approach for the integrated control of animal gastrointestinal (GI) parasites. However, literature addressing the possible interference of antiparasitic drugs on the performance of these fungi is still scarce. This research aimed to assess the in vitro susceptibility of six native coccidicidal fungi isolates of the species Mucor circinelloides and one Mucor lusitanicus isolate to several antiparasitic drugs commonly used to treat GI parasites’ infections in birds, namely anthelminthics such as Albendazole, Fenbendazole, Levamisole and Ivermectin, and anticoccidials such as Lasalocid, Amprolium and Toltrazuril (drug concentrations of 0.0078–4 µg/mL), using 96-well microplates filled with RPMI 1640 medium, and also on Sabouraud Agar (SA).
Results
This research revealed that the exposition of all Mucor isolates to the tested anthelminthic and anticoccidial drug concentrations did not inhibit their growth. Fungal growth was recorded in RPMI medium, after 48 h of drug exposure, as well as on SA medium after exposure to the maximum drug concentration.
Conclusions
Preliminary findings from this research suggest the potential compatibility of these Mucor isolates with antiparasitic drugs for the integrated control of avian intestinal parasites. However, further in vitro and in vivo studies are needed to confirm this hypothesis.
... are both found in water, food, air, and soil [9]. In contrast, the fungi from the order Mucorales are facultative parasites, regularly originating from soil, compost piles, animal fecal matter, decaying organic matter, agricultural debris, and can therefore be considered opportunistic pathogens for plants, animals, and humans [10]. For Aspergillus spp., climatic differences regarding temperature and humidity play a very important role in the incidence of the disease, while in Fusarium spp., the affinity for marine or river environments makes it more common in the northern temperate regions [9]. ...
... For Aspergillus spp., climatic differences regarding temperature and humidity play a very important role in the incidence of the disease, while in Fusarium spp., the affinity for marine or river environments makes it more common in the northern temperate regions [9]. Mucormycosis is also dependent upon climatic conditions, studies showing a strong connection between seasonal variations and an increase in the number of cases of mucormycosis during August to November [10]. ...
... The former, once it reaches the lungs, germinates into hyphae in an uncontrolled manner, spreading fast towards a potentially invasive form of the mold [34]. The latter colonizes the respiratory or the gastrointestinal system, waiting for the favorable ground of the host in order to cause infection [10]. In contrast, Fusarium spp. ...
Fungi play a vital role in ensuring a physiological balance in the surrounding environments, interacting closely with humans, plants, and animals. While most of the time their contribution is beneficial, occasionally, they can become harmful, especially in patients with weakened immune systems. The work at hand aims to present the most common fungal pathogens involved in invasive infections, focusing on fungi that are present in the tropical and temperate areas of the world. While in the former, due to the humid climate, most fungal infections are caused by dimorphic fungi such as Coccidioides spp., Blastomyces spp., Histoplasma spp., Emergomyces spp. and Paracoccidioides spp., in the latter, after Candida spp., the most frequent fungi that are involved in disseminated mycosis are Aspergillus spp., Fusarium spp. and species from the order Mucorales. Nowadays, the etiology, severity, and number of cases of fungal diseases are starting to rise significantly. There are no exact reasons reported for this increase, but several factors are thought to be incriminated: the expansion of the range of medical conditions that constitute risk factors for developing the disease, an improvement in the available diagnostic methods, the commodity offered by modern traveling services associated with the lack of an available vaccine against fungal infections, as well as climatic influences. All the above-mentioned aspects consequently caused infections that used to be endemic to be spread worldwide. Therefore, it is of critical importance to understand the epidemiology, clinical manifestations of fungi induced diseases, virulence factors, and diagnosis for each of those pathogens.
... Mucormycosis is a life-threatening infection that is difficult to treat since the causing agents affect mainly immunocompromised patients and are known to be intrinsically resistant to several antifungal drugs, including most azoles [31]. In this context, new options for mucormycosis treatment are needed, and drug repurposing has emerged as an interesting approach. ...
Mucorales are a group of non-septated filamentous fungi widely distributed in nature, frequently associated with human infections, and are intrinsically resistant to many antifungal drugs. For these reasons, there is an urgent need to improve the clinical management of mucormycosis. Miltefosine, which is a phospholipid analogue of alkylphosphocholine, has been considered a promising repurposing drug to be used to treat fungal infections. In the present study, miltefosine displayed antifungal activity against a variety of Mucorales species, and it was also active against biofilms formed by these fungi. Treatment with miltefosine revealed modifications of cell wall components, neutral lipids, mitochondrial membrane potential, cell morphology, and the induction of oxidative stress. Treated Mucorales cells also presented an increased susceptibility to SDS. Purified ergosterol and glucosylceramide added to the culture medium increased miltefosine MIC, suggesting its interaction with fungal lipids. These data contribute to elucidating the effect of a promising drug repurposed to act against some relevant fungal pathogens that significantly impact public health.
... The absence of fermentation in the M. lusitanicus M5 strain, which depends on oxidative metabolism, correlates with higher virulence in the blood serum at levels comparable to those of SS from known virulent Mucorales species, such as R. arrhizus and L. corymbifera [39]. This finding suggests that Mucorales species associated with mucormycosis may have a greater intrinsic mitochondrial metabolism than species such as M. lusitanicus. ...
This study analyzed the role of blood serum in enhancing the mitochondrial metabolism and virulence of Mucorales through rhizoferrin secretion. We observed that the spores of clinically relevant Mucorales produced in the presence of serum exhibited higher virulence in a heterologous infection model of Galleria mellonella. Cell-free supernatants of the culture broth obtained from spores produced in serum showed increased toxicity against Caenorhabditis elegans, which was linked with the enhanced secretion of rhizoferrin. Spores from Mucoralean species produced or germinated in serum showed increased respiration rates and reactive oxygen species levels. The addition of non-lethal concentrations of potassium cyanide and N-acetylcysteine during the aerobic or anaerobic growth of Mucorales decreased the toxicity of the cell-free supernatants of the culture broth, suggesting that mitochondrial metabolism is important for serum-induced virulence. In support of this hypothesis, a mutant strain of Mucor lusitanicus that lacks fermentation and solely relies on oxidative metabolism exhibited virulence levels comparable to those of the wild-type strain under serum-induced conditions. Contrary to the lower virulence observed, even in the serum, the ADP-ribosylation factor-like 2 deletion strain exhibited decreased mitochondrial activity. Moreover, spores produced in the serum of M. lusitanicus and Rhizopus arrhizus that grew in the presence of a mitophagy inducer showed low virulence. These results suggest that serum-induced mitochondrial activity increases rhizoferrin levels, making Mucorales more virulent.
... Overall, and regarding the V. index, five Mucor isolates showed a worrying V. index (M1, M2, M3, M5, M6), being able to produce half or more than half of the virulence factors studied. This result is not surprising, since Mucorales express several known virulence factors that can contribute to their pathogenicity and immune evasion [63]. ...
Due to poisoning and decline in the food resources of Eurasian vultures, there has been a rise in the number of Griffon (Gyps fulvus) and Cinereous vultures (Aegypius monachus) needing veterinary care. In captivity, vultures often develop oral and other infectious diseases which can affect their survival and the probability of reintroduction in the wild. Therefore, it is important to characterize relevant microbial species present in the oral cavity of vultures, such as Mucor spp. In this work, seven Mucor spp. isolates previously obtained from Gyps fulvus and Aegypius monachus oral swabs collected at two rehabilitation centers in Portugal were characterized regarding their pathogenic enzymatic profile and antimicrobial activity. Isolates were identified by macro and microscopic observation, and PCR and ITS sequencing. Their antimicrobial activity was determined using a collection of pathogenic bacteria and two yeast species. Results showed that 86% of the isolates produced α-hemolysis, 71% expressed DNase, 57% produce lecithinase and lipase, 29% expressed gelatinase, and 29% were biofilm producers. Four isolates showed inhibitory activity against relevant human and veterinary clinical isolates, including Escherichia coli, Enterococcus faecium, Neisseria zoodegmatis, and Staphylococcus aureus. In conclusion, accurate management programs should consider the benefits and disadvantages of Mucor spp. presence in the oral mucosa.
... The basic tools for the identification of this disease include a CT scan, positron emission tomography, computed tomography with 18F-fluorodeoxyglucose, microscopy, mass spectroscopy, and serological tests like ELISA, PCR, DNA sequencing, etc. For the diagnosis of pulmonary mucormycosis, quantitative PCR, a histopathological study, was found to be the most effective method for the detection of the causative organism (Hassan 2019;Skiada 2018). ...
... • The ability of the micro-organism to escape the host immune defense and survive inside the host cell. • Agitation of the host immune system and damage the host cell (Hassan 2019). ...
... • Disseminated mucormycosis-leading to medical complications. • Uncommon renal infection (Hassan 2019). ...
The COVID-19 survivors and long-term steroid administered patients exhibit a variety of fungal co-infections. The lives of COVID-19 patients and survivors are hampered by fungal species of the genera Candida, Aspergillus, and Mucor. There have been cases of mucormycosis, aspergillosis, and candidiasis in COVID-19 patients. The treatments given to these opportunistic fungal infections include polyene like amphotericin B, azoles including imidazoles like ketoconazole, miconazole, and triazoles like fluconazole, voriconazole, itraconazole, Echinocandin derivatives like- caspofungin, micafungin, immunomodulatory therapy, granulocyte transfusion, etc. A successful recovery and the reduction of fatalities depend on prompt diagnosis and treatment. To reduce mortality, advanced techniques to identify such uncommon infections at a very early stage are necessary. This review's goal is to provide a summary of the systemic and superficial opportunistic fungal infections that the COVID-19 survivors were dealing with, including information on illness incidence, pathogenicity, and treatment.
... Mucormycosis is considered to be a very destructive invasive fungal disease [5]. Human mucormycoses are caused by a wide range of fungal pathogens linked to the mucorales, including Rhizopus, Mucor, and Lichtheimia corymbifera and Syncephalastrum [6]. gold, platinum, and silver by the use of a green approach, which involved the extraction of leaf material from Lamii albi flos. ...
Metal nanoparticles are assumed to be a new generation of biologically active materials. The integrations between more than one metal are synergetic multifunctional features. In the current study, trimetallic copper–selenium–zinc oxide nanoparticles (Tri-CSZ NPs) were successfully mycosynthesized using Aspergillus niger through an ecofriendly method for the first time. The biosynthesis of the particles was characterized using physiochemical and topographical analysis. The physiochemical analysis included Fourier transform infrared spectroscopy (FTIR), which affirmed that the biosynthesis of Tri-CSZ NPs relies on the functional groups of fungal filtrates. Additionally, the UV–visible and X-ray diffraction patterns were proposed for the formation of Tri-CSZ NPs; moreover, topography analysis confirmed that the micromorphology of the nanoparticles were similar to a stick, with ends having a tetragonal pyramid shape, and with an average nanosize of about 26.3 ± 5.4 nm. Cytotoxicity results reveled that the Tri-CSZ NPs have no cytotoxicity on the human normal cell line Wi 38 at low concentrations, where the IC50 was 521 µg/mL. Furthermore, the antifungal activity of the Tri-CSZ NPs was evaluated. The antifungal results revealed that the Tri-CSZ NPs have promising antifungal activity against Mucor racemosus, Rhizopus microsporus, Lichtheimia corymbifera, and Syncephalastrum racemosum, where the minimum inhibitory concentrations (MICs) were 1.95, 7.81, 62.5, and 3.9 µg/mL, and the minimum fungicidal concentrations (MFCs) were 250, 62.5, 125, and 1000 µg/mL, respectively. In conclusion, Tri-CSZ NPs were successfully mycosynthesized using A. niger, which have a promising antifungal activity against fungi causing mucormycosis.
... Treatment of mucormycosis is extremely challenging due to the different manifestations of the infection (such as cutaneous, pulmonary, or rhino-orbito-cerebral mucormycosis) and the diverse causative agents. Furthermore, treatment often differs in duration and may require multidisciplinary approaches, such as surgery and other symptomatic therapies (1). The main approach is to combine antifungal therapy with surgical interventions, which can increase the survival rate from 30 to 70% (2). ...
Certain members of the order Mucorales can cause a life-threatening, often-fatal systemic infection called mucormycosis. Mucormycosis has a high mortality rate, which can reach 96 to 100% depending on the underlying condition of the patient. Mucorales species are intrinsically resistant to most antifungal agents, such as most of the azoles, which makes mucormycosis treatment challenging. The main target of azoles is the lanosterol 14α-demethylase (Erg11), which is responsible for an essential step in the biosynthesis of ergosterol, the main sterol component of the fungal membrane. Mutations in the erg11 gene can be associated with azole resistance; however, resistance can also be mediated by loss of function or mutation of other ergosterol biosynthetic enzymes, such as the sterol 24-C-methyltransferase (Erg6). The genome of Mucor lusitanicus encodes three putative erg6 genes (i.e., erg6a, erg6b, and erg6c). In this study, the role of erg6 genes in azole resistance of Mucor was analyzed by generating and analyzing knockout mutants constructed using the CRISPR-Cas9 technique. Susceptibility testing of the mutants suggested that one of the three genes, erg6b, plays a crucial role in the azole resistance of Mucor. The sterol composition of erg6b knockout mutants was significantly altered compared to that of the original strain, and it revealed the presence of at least four alternative sterol biosynthesis pathways leading to formation of ergosterol and other alternative, nontoxic sterol products. Dynamic operation of these pathways and the switching of biosynthesis from one to the other in response to azole treatment could significantly contribute to avoiding the effects of azoles by these fungi. IMPORTANCE The fungal membrane contains ergosterol instead of cholesterol, which offers a specific point of attack for the defense against pathogenic fungi. Indeed, most antifungal agents target ergosterol or its biosynthesis. Mucormycoses-causing fungi are resistant to most antifungal agents, including most of the azoles. For this reason, the drugs of choice to treat such infections are limited. The exploration of ergosterol biosynthesis is therefore of fundamental importance to understand the azole resistance of mucormycosis-causing fungi and to develop possible new control strategies. Characterization of sterol 24-C-methyltransferase demonstrated its role in the azole resistance and virulence of M. lusitanicus. Moreover, our experiments suggest that there are at least four alternative pathways for the biosynthesis of sterols in Mucor. Switching between pathways may contribute to the maintenance of azole resistance.
... With an aging population, the increased number of immunocompromised patients, and the recent COVID-19 pandemic, the number of individuals susceptible to Mucorales infections is on the rise [3]. The noticeable increase in mucormycosis cases, a mortality rate of 90% for disseminated infections, and the absence of effective antifungal treatments have triggered widespread concern regarding this emerging disease [4,5]. In addition, advancements in diagnostic techniques have uncovered an alarming number of cases of mucormycosis among immunocompetent/otherwise healthy individuals [6]. ...
The classification of Mucorales encompasses a collection of basal fungi that have traditionally demonstrated an aversion to modern genetic manipulation techniques. This aversion led to a scarcity of knowledge regarding their biology compared to other fungal groups. However, the emergence of mucormycosis, a fungal disease caused by Mucorales, has attracted the attention of the clinical field, mainly because available therapies are ineffective for decreasing the fatal outcome associated with the disease. This revitalized curiosity about Mucorales and mucormycosis, also encouraged by the recent COVID-19 pandemic, has spurred a significant and productive effort to uncover their mysteries in recent years. Here, we elaborate on the most remarkable breakthroughs related to the recently discovered genetic advances in Mucorales and mucormycosis. The utilization of a few genetic study models has enabled the identification of virulence factors in Mucorales that were previously described in other pathogens. More notably, recent investigations have identified novel genes and mechanisms controlling the pathogenic potential of Mucorales and their interactions with the host, providing fresh avenues to devise new strategies against mucormycosis. Finally, new study models are allowing virulence studies that were previously hampered in Mucorales, predicting a prolific future for the field.
