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Global Fungal Burden

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... Fortunately, many cases are aymptomatic to mild mucocutaneous infections rather than potentially life-threatening systemic infections [99]. Even so, nearly a billion people on our planet have skin, nail and hair fungal infections; tens of millions suffer from mucosal candidiasis; and more than 150 million fall victim to debilitating and potentially serious fungal diseases [99][100][101][102]. ...
... Among the latter conditions are roughly 3,000,000 cases of chronic pulmonary aspergillosis, about 223,100 cases of cryptococcal meningitis complicating HIV/AIDs, about 700,000 cases of invasive candidiasis, about 500,000 cases of pneumocystis pneumonia, about 250,000 cases of invasive aspergillosis, about 100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma, and about 1,000,000 cases of fungal keratitis per year [99][100][101][102]. Notably, over 1.6 million people die each year from their disease, which is comparable to the mortality due to tuberculosis and more than three-fold that caused by malaria [99]. ...
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Fungi are unicellular or multicellular thick-walled eukaryotic organisms that are not capable of photosynthesis and are placed in a biological kingdom of their own. They are ubiquitous in our environment, and include tens of thousands, perhaps even millions of species of yeasts, rusts, smuts, mildews, molds, and mushrooms. Together with bacteria, fungi are the principal decomposers of plant materials such as cellulose and lignin, fulfilling vital ecological functions in all terrestrial habitats. Some species of fungi are also of major importance in households (for instance, as foods such as edible mushrooms), medicine (for instance, as producers of antibiotics such as penicillin), and industry (for instance, for making bread, wine, and cheese). About 300 fungal species cause infections in humans, varying from relatively harmless skin complaints such as pityriasis versicolor to potentially life-threatening systemic syndromes such as candidiasis. Fortunately, a broad armamentarium of efficacious antifungal drugs has been developed, ranging from topical nystatin to parenteral amphotericin B. In addition, most, if not all traditional medical systems throughout the world have identified a large assortment of plant-based remedies for treating these infections. This also holds true for the multi-ethnic and multicultural Republic of Suriname (South America), where plant-based traditional medicines are abundantly used, either alone or in conjunction with allopathic medications. This monograph extensively addresses nine plants that are traditionally used for treating fungal infections in Suriname, and explains the phytochemical and pharmacological rationales for these applications. These sections are preceded by some general observations about the Fungal Kingdom; a few words about the characteristics of fungi, their taxonomy, and their significance to humans; information about fungal infections as well as the available forms of treatment; and some details about Suriname including health aspects, the health care structure, and the main fungal infections in the country. The monograph is concluded with an evaluation of the status of the Surinamese herbal antifungal substances and the previsions of developing them into mainstream antifungal formulations.
... For patients undergoing haematopoietic stem cell transplantation (HSCT) and in particular allogeneic grafts, invasive aspergillosis (IA) is an important cause of pulmonary related mortality (3). Chronic and allergic forms are rarely life threatening, however, they are estimated to have global burdens of approximately 1.2 million and 4.8 million people respectively (4,5). Moreover, they may affect patients with an intact immune system but have other medical co-morbidities placing them at a higher risk of fungal sensitization and subsequent allergic disease. ...
... To the solution was added N,N-Diisopropylethylamine (1. 5 2'-((3,5-dichloro-4-(1,2,4-triazol-3yl)phenyl)azanediyl)bis(ethan-1-ol), Compound 3 2,6-dichloro-4-nitrobenzamide (1 g, 4.25 mmol) was dissolved in ethanol (12 ml) followed by the addition of tin (II) chloride dihydrate (4.8 mg, 21.30 mmol). The resulting solution was refluxed at 70ºC overnight at which point the solution was cooled, poured into ice water (50 ml) and pH adjusted (to pH ~8-9) using 4N aqueous sodium hydroxide, where it was allowed to stir for 30 min. ...
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Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment, including host defense responses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. Because this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N -acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Δ gna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective sub-micromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus .
... Increase in numbers of cutaneous fungal infections is being observed around the world. Approximately nearly a billion people are estimated to have skin, nail or hair fungal infections [1,2]. Dermatomycoses occur in every age group and can significantly decrease quality of life. ...
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Introduction: An increase in numbers of cutaneous fungal infections is being observed around the world. Dermatomycoses occur in every age group and can significantly decrease quality of life. Examining the prevalence and epidemiological trends of cutaneous fungal infections is necessary for developing new effective preventive, diagnostic and therapeutic methods. Many factors can influence the growth and patterns of global spread of the different species of fungi. Aim: To investigate the differences between the prevalence of dermatophytes and cutaneous fungal infections observed at two mycological laboratories and their plausible causes. Material and methods: Mycological examination was performed in 7324 patients in Gdansk, Poland and in 4729 patients in Grodno, Belarus who exhibited clinical signs and symptoms of cutaneous fungal infections. Direct preparations was made in 20% KOH with 40% DMSO. Additionally cultures were prepared on modified Sabouraud dextrose agar. Results: Dermatophytes were cultured in 642 (53.58%) cases in Gdansk. The most common species of dermatophytes were Trichophyton rubrum (306 cases), Trichophyton mentagrophytes var. granulosum (193 cases) and Microsporum canis (127 cases). Yeasts were isolated in 531 (44.40%) cases out of which Candida albicans was the most frequently identified in 323 cases. Similarly, dermatophytes were the most common in 1158 (68.72%) cases in Grodno. Candida were isolated in 527 (31.28%) cases. Analysing the localization of dermatomycoses onychomycosis was observed in majority of the infected patients in Gdansk. In Grodno the most common location of superficial cutaneous infection was tinea corporis In the Gdansk region dermatomycoses were observed in 688 female patients and in 508 male patients. In Grodno the prevalence is inverted with the majority of cases observed in 921 males and 764 females. Conclusions: The prevalence of superficial fungal infections is higher in Grodno, Belarus when compared to Gdansk, Poland. Similarly, dermatophytes were most commonly observed in both Laboratories.
... This high number is explained by the rise of at-risk populations including asthma, tuberculosis, acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease (COPD), cancer, and immunosuppressed patients on chemotherapy [6][7][8][9]. Many factors such as socioeconomic conditions, hospital infection practices, unrestrained use of corticosteroids and antibiotics, geographic region, and cultural habits contribute to a marked variability of the incidence and prevalence of fungal disease worldwide [8,[10][11][12][13][14][15]. ...
Article
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Fungal infections are an increasingly important public health issue, yet accurate statistics on fungal burden worldwide and in Kuwait are scarce. Here we estimate the incidence and prevalence of fungal infections in Kuwait. Population statistics from 2018 collected by the Public Authority for Civil Information were used, as well as data from the Ministry of Health. A literature search for Kuwait data on mycotic diseases and population at risk (chronic obstructive pulmonary disease, HIV infection/AIDS, cancer, and transplant patients) was conducted. The population in 2018 was estimated at 4,226,920 million people: 1,303,246 million Kuwaitis and 2,923,674 million expatriates. We determined the annual burden of serious fungal infections number (per 100,000) from high to low based on earlier reported fungal rates for populations at risk: recurrent Candida vaginitis 54,842 (2595); severe asthma with fungal sensitisation 10,411 (246); allergic bronchopulmonary aspergillosis, 7887 (187); chronic pulmonary aspergillosis 995 (21.3); invasive aspergillosis 704 (16.7); fungal keratitis 654 (15.5); candidaemia 288 (6.8); Candida peritonitis 63 (3.5) and oesophageal candidiasis in HIV 33 (0.8). Besides identifying rising new risk groups and expanding reports on antifungal resistance, surveillance programs and further epidemiological studies are needed to achieve more precise assessments of fungal disease epidemiology and correlated morbidity and mortality.
... Fungal pathogens have long been associated with infectious diseases in humans and other mammals [1][2][3][4]. At least one-quarter of the human population will experience a superficial mucosal fungal infection during their lifetime, however, life-threatening infections occur less frequently but now at an increasing rate due to medical advancements and ability of populations to have longer lifespans and patients to survive trauma and immunotherapies [1,5].To date, no vaccines have been approved for human use to halt the rise of fungal infections and so our ability to understand fungal disease and to develop novel antifungal interventions is vital. ...
Article
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Pathogenic fungi represent an increasing infectious disease threat to humans, especially with an increasing challenge of antifungal drug resistance. Over the decades, numerous tools have been developed to expedite the study of pathogenicity, initiation of disease, drug resistance and host-pathogen interactions. In this review, we highlight advances that have been made in the use of molecular tools using CRISPR technologies, RNA interference and transposon targeted mutagenesis. We also discuss the use of animal models in modelling disease of human fungal pathogens, focusing on zebrafish, the silkworm, Galleria mellonella and the murine model.
... For patients undergoing haematopoietic stem cell transplantation (HSCT) and in particular allogeneic grafts, invasive aspergillosis (IA) is an important cause of pulmonary related mortality 3 . Chronic and allergic forms are rarely life threatening, however, they are estimated to have global burdens of approximately 1.2 million and 4.8 million people respectively 4,5 . Moreover, they may affect patients with an intact immune system but have other medical co-morbidities placing them at a higher risk of fungal sensitisation and subsequent allergic disease. ...
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Aspergillus fumigatus is a human opportunistic fungal pathogen with a cell wall that protects it from the extracellular environment. Chitin, an essential cell wall component, is synthesised from UDP-GlcNAc that is produced by the hexosamine biosynthetic pathway. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. Deletion of GNA1 results in loss of viability and disruption of the cell wall, phenotypes that can be rescued by the product of the enzyme. In a murine model of aspergillosis, the Δgna1 mutant strain attenuates virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the active site and can be optimised to a selective sub-micromolar binder. Taken together, we have provided genetic, structural and chemical evidence for Gna1 as an antifungal target in Aspergillus fumigatus.
... Recent global estimates found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDs, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually (Table 1) [1,[7][8][9]. Here we address these and estimates for the many countries that contribute to these global figures. ...
Article
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Fungal diseases kill more than 1.5 million and affect over a billion people. However, they are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable. Serious fungal infections occur as a consequence of other health problems including asthma, AIDS, cancer, organ transplantation and corticosteroid therapies. Early accurate diagnosis allows prompt antifungal therapy; however this is often delayed or unavailable leading to death, serious chronic illness or blindness. Recent global estimates have found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDS, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually. Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated the estimation of the burden of serious fungal infections country by country for over 5.7 billion people (>80% of the world’s population). These studies have shown differences in the global burden between countries, within regions of the same country and between at risk populations. Here we interrogate the accuracy of these fungal infection burden estimates in the 43 published papers within the LIFE initiative.
Chapter
Invasive and disseminated Candida infections have become a major source of morbidity and mortality in neutropenic and nonneutropenic surgical intensive care patients. The incidence of Candida has increased: it is now the fourth most often isolated pathogen in bloodstream infections. After extended intraabdominal surgery and especially in emergency intraabdominal infection the abdomen is the predominant focus for candida infection. Intraabdominal candidiasis (IAC) is the predominant type of invasive candidiasis after candidemia. IAC is associated with mortality rates around 25–60%. Some studies have demonstrated almost a double mortality rate (48% versus 28%) in critically ill surgical patients with nosocomial fungal peritonitis compared to those without fungal infection. The diagnosis of postoperative candida infections is difficult because clinical signs and laboratory findings are unspecific. The decisive factors for a favorable outcome of infected patients are early diagnosis, adequate source control, as well as a prompt and appropriate anti-infective therapy.
Article
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Fungal pathogens are an increasingly important cause of human disease and mortality, and Candida albicans is among the most common causes of fungal disease. Studying this important fungal pathogen requires a comprehensive genetic toolkit to establish how different genetic factors play roles in the biology and virulence of this pathogen. Here, we developed a CRISPR-based genetic regulation platform to achieve targeted repression of C. albicans genes. This CRISPR interference (CRISPRi) technology exploits a nuclease-dead Cas9 protein (dCas9) fused to transcriptional repressors. The dCas9 fusion proteins pair with a guide RNA to target genetic promoter regions and to repress expression from these genes. We demonstrated the functionality of this system for repression in C. albicans and show that we can apply this technology to repress essential genes. Taking the results together, this work presents a new technology for efficient genetic repression in C. albicans , with important applications for genetic analysis in this fungal pathogen.
Article
The study of fungal pathogens is of immediate importance, yet progress is hindered by the technical challenges of genetic manipulation. For Candida species, their inability to maintain plasmids, unusual codon usage, and inefficient homologous recombination are among the obstacles limiting efficient genetic manipulation. New advances in genomic biotechnologies—particularly CRISPR-based tools—have revolutionized genome editing for many fungal species. Here, we present a protocol for CRISPR–Cas9-based manipulation in Candida albicans using a modified gene-drive-based strategy that takes ~1 month to complete. We detail the generation of Candida-optimized Cas9-based plasmids for gene deletion, an efficient transformation protocol using C. albicans haploids, and an optimized mating strategy to generate homozygous single- and double-gene diploid mutants. We further describe protocols for quantifying cell growth and analysis pipelines to calculate fitness and genetic interaction scores for genetic mutants. This protocol overcomes previous limitations associated with genetic manipulation in C. albicans and advances researchers’ ability to perform genetic analysis in this pathogen; the protocol also has broad applicability to other mating-competent microorganisms. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
Chapter
The term candidosis or candidiasis comprises several categories of infection: systemic or invasive Candida infections/diseases (IC), such as acute disseminated candidosis, chronic disseminated candidosis (CDC) and candidaemia as well as superficial (muco-cutaneous) Candida infections. According to the recent consensus definition the term “fungal infection” should be replaced by “fungal disease”. Candidaemia is the most frequent manifestation of systemic Candida infection. The serious prognosis associated with candidaemia is highlighted by a recent survey of 60 cases with candidaemia due to C. albicans (n = 38) and non-C. albicans (n = 22): 8% developed severe sepsis and 27% septic shock. The all-cause mortality was 42%. Candidaemia is most often observed in non-granulocytopenic patients after abdominal surgery or catheter-related infection with secondary blood stream infection. Potential further manifestations of invasive disease are Candida oesophagitis (in the past often classified as muco-cutaneous candidosis), peritonitis, urinary tract infections. Less frequently, endocarditis, meningitis/meningoencephalitis or osteomyelitis are manifestations of acute disseminated candidosis.
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