scholarly journals SOD5 is the Prototype of a New Class of Cu-only Superoxide Dismutases

2014 ◽  
Vol 70 (a1) ◽  
pp. C809-C809
Author(s):  
Ahmad Galaleldeen ◽  
Julie Gleason ◽  
Diane Cabelli ◽  
John Hart ◽  
Valeria Culotta
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Superoxide Dismutases ◽  
X Ray Diffraction ◽  
Mucosal Surfaces ◽  
Copper Site ◽  
Zinc Binding Site ◽  
Life Threatening ◽  
Copper Zinc ◽  
Systemic Infections

Superoxide dismutases (SODs) are antioxidant enzymes that catalyze the dismutation of superoxide into molecular oxygen and hydrogen peroxide. Candida albicans is a polymorphic fungus that causes the majority of fungal infections in humans. In the immunocompetent population, colonization of C. albicans can result in acute infections of the mucosal surfaces both in the oral and genital cavities, however, immunocompromised individuals encounter life-threatening systemic infections. Several factors contribute to the pathogenesis of C. albicans including the expression of SOD5; a postulated copper-zinc SOD. SOD5 enables C. albicans to evade the immune response of the host, namely the oxidative burst. In the absence of SOD5, reactive oxygen species (ROS) accumulate and C. albicans exhibit a severe loss in viability. Our studies sought to examine the crystal structure of SOD5. The protein was overexpressed in E. coli and due to its insolubility; it was denatured, refolded, and further purified. Following protein purification, a sedimentation velocity experiment was performed and the data revealed that SOD5 is a monomeric protein in solution. The structure was then determined using single crystal X-ray diffraction. The structure of SOD5 confirms that it is a prototype of monomeric SODs possessing a copper-only active site and lacking a zinc binding site. In addition, this protein was devoid of the electrostatic loop that typically characterizes all SOD1s. The SOD5 copper site is solvent accessible, cupped in an electrostatic architecture that could serve in superoxide guidance. SOD5-like proteins are widespread among fungal pathogens and appear adapted for the metal and oxidative challenges at the host-pathogen interface.

scholarly journals Role for IL-1 Family Cytokines in Fungal Infections

2021 ◽  
Vol 12 ◽  
Author(s):  
James S. Griffiths ◽  
Giorgio Camilli ◽  
Natalia K. Kotowicz ◽  
Jemima Ho ◽  
Jonathan P. Richardson ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Systemic Disease ◽  
Severe Disease ◽  
Life Threatening ◽  
Current Therapies ◽  
Immunotherapy Target ◽  
Systemic Infections ◽  
Fungal Immunity ◽  
Anti Fungal

Fungal pathogens kill approximately 1.5 million individuals per year and represent a severe disease burden worldwide. It is estimated over 150 million people have serious fungal disease such as recurrent mucosal infections or life-threatening systemic infections. Disease can ensue from commensal fungi or new infection and involves different fungal morphologies and the expression of virulence factors. Therefore, anti-fungal immunity is complex and requires coordination between multiple facets of the immune system. IL-1 family cytokines are associated with acute and chronic inflammation and are essential for the innate response to infection. Recent research indicates IL-1 cytokines play a key role mediating immunity against different fungal infections. During mucosal disease, IL-1R and IL-36R are required for neutrophil recruitment and protective Th17 responses, but function through different mechanisms. During systemic disease, IL-18 drives protective Th1 responses, while IL-33 promotes Th2 and suppresses Th1 immunity. The IL-1 family represents an attractive anti-fungal immunotherapy target. There is a need for novel anti-fungal therapeutics, as current therapies are ineffective, toxic and encounter resistance, and no anti-fungal vaccine exists. Furthering our understanding of the IL-1 family cytokines and their complex role during fungal infection may aid the development of novel therapies. As such, this review will discuss the role for IL-1 family cytokines in fungal infections.

scholarly journals Overview of medically important antifungal azole derivatives.

1988 ◽  
Vol 1 (2) ◽  
pp. 187-217 ◽  
Author(s):  
R A Fromtling
Keyword(s):  
Adverse Reactions ◽  
Fungal Infections ◽  
Chemotherapeutic Agents ◽  
Skin Infections ◽  
Life Threatening ◽  
Major Chemical ◽  
Systemic Infections ◽  
Selection Of

Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

scholarly journals Vaccines for human fungal diseases: close but still a long way to go

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Lorena V. N. Oliveira ◽  
Ruiying Wang ◽  
Charles A. Specht ◽  
Stuart M. Levitz
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Global Burden ◽  
Nucleic Acid Vaccines ◽  
Life Threatening ◽  
Human Use ◽  
Common Antigens ◽  
Mycotic Infections

AbstractDespite the substantial global burden of human fungal infections, there are no approved fungal vaccines to protect at risk individuals. Here, we review the progress that has been made and the challenges that lie ahead in the quest towards efficacious fungal vaccines. In mouse studies, protection has been achieved with vaccines directed against fungal pathogens, including species of Candida, Cryptococcus, and Aspergillus, that most commonly cause life-threatening human disease. Encouraging results have been obtained with vaccines composed of live-attenuated and killed fungi, crude extracts, recombinant subunit formulations, and nucleic acid vaccines. Novel adjuvants that instruct the immune system to mount the types of protective responses needed to fight mycotic infections are under development. Candidate vaccines include those that target common antigens expressed on multiple genera of fungi thereby protecting against a broad range of mycoses. Encouragingly, three vaccines have reached human clinical trials. Still, formidable obstacles must be overcome before we will have fungal vaccines licensed for human use.

Progress and prospects for targeting Hsp90 to treat fungal infections

Parasitology ◽  
2014 ◽  
Vol 141 (9) ◽  
pp. 1127-1137 ◽  
Author(s):  
AMANDA VERI ◽  
LEAH E. COWEN
Keyword(s):  
Drug Resistance ◽  
Anticancer Agents ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Effective Combination ◽  
New Strategy ◽  
Life Threatening ◽  
Hsp90 Chaperone ◽  
Hsp90 Function

SummaryFungal pathogens pose a major threat to human health worldwide. They infect billions of people each year, leading to at least 1·5 million deaths. Treatment of fungal infections is difficult due to the limited number of clinically useful antifungal drugs, and the emergence of drug resistance. A promising new strategy to enhance the efficacy of antifungal drugs and block the evolution of drug resistance is to target the molecular chaperone Hsp90. Pharmacological inhibitors of Hsp90 function that are in development as anticancer agents have potential to be repurposed as agents for combination antifungal therapy for some applications, such as biofilm infections. For systemic infections, however, effective combination therapy regimens may require Hsp90 inhibitors that can selectively target Hsp90 in the pathogen, or alternate strategies to compromise function of the Hsp90 chaperone machine. Selectively impairing Hsp90 function in the pathogen could in principle be achieved by targeting Hsp90 co-chaperones or regulators of Hsp90 function that are more divergent between pathogen and host than Hsp90. Antifungal combination therapies could also exploit downstream effectors of Hsp90 that are critical for fungal drug resistance and virulence. Here, we discuss the progress and prospects for establishing Hsp90 as an important therapeutic target for life-threatening fungal infections.

scholarly journals In vitro infection models to study fungal-host interactions

2021 ◽  
Author(s):  
Antonia Last ◽  
Michelle Maurer ◽  
Alexander S Mosig ◽  
Mark S Gresnigt ◽  
Bernhard Hube
Keyword(s):  
Fungal Infections ◽  
In Vitro Models ◽  
Fungal Host ◽  
Host Interactions ◽  
Mucosal Surfaces ◽  
Life Threatening ◽  
On Chip ◽  
Fungal Interactions

Abstract Fungal infections (mycoses) affect over a billion people per year. Approximately two million of these infections are life-threatening, especially for patients with a compromised immune system. Fungi of the genera Aspergillus, Candida, Histoplasma, and Cryptococcus are opportunistic pathogens that contribute to a substantial number of mycoses. To optimize the diagnosis and treatment of mycoses, we need to understand the complex fungal-host interplay during pathogenesis, the fungal attributes causing virulence, and how the host resists infection via immunological defenses. In vitro models can be used to mimic fungal infections of various tissues and organs and the corresponding immune responses at near-physiological conditions. Furthermore, models can include fungal interactions with the host-microbiota to mimic the in vivo situation on skin and mucosal surfaces. This article reviews currently used in vitro models of fungal infections ranging from cell monolayers to microfluidic 3D organ-on-chip (OOC) platforms. We also discuss how OOC models can expand the toolbox for investigating interactions of fungi and their human hosts in the future.

scholarly journals An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

2020 ◽  
Vol 6 (1) ◽  
pp. 23 ◽  
Author(s):  
Sara B. Salazar ◽  
Rita S. Simões ◽  
Nuno A. Pedro ◽  
Maria Joana Pinheiro ◽  
Maria Fernanda N. N. Carvalho ◽  
...  
Keyword(s):  
Candida Species ◽  
Fungal Infections ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Mortality And Morbidity ◽  
Synthetic Chemicals ◽  
Mucosal Surfaces ◽  
Life Threatening ◽  
Resistant Strains ◽  
Novel Approaches

Fungal infections and, in particular, those caused by species of the Candida genus, are growing at an alarming rate and have high associated rates of mortality and morbidity. These infections, generally referred as candidiasis, range from common superficial rushes caused by an overgrowth of the yeasts in mucosal surfaces to life-threatening disseminated mycoses. The success of currently used antifungal drugs to treat candidiasis is being endangered by the continuous emergence of resistant strains, specially among non-albicans Candida species. In this review article, the mechanisms of action of currently used antifungals, with emphasis on the mechanisms of resistance reported in clinical isolates, are reviewed. Novel approaches being taken to successfully inhibit growth of pathogenic Candida species, in particular those based on the exploration of natural or synthetic chemicals or on the activity of live probiotics, are also reviewed. It is expected that these novel approaches, either used alone or in combination with traditional antifungals, may contribute to foster the identification of novel anti-Candida therapies.

scholarly journals Beauvericin Potentiates Azole Activity via Inhibition of Multidrug Efflux, BlocksC. albicansMorphogenesis, and is Effluxed via Yor1 and Circuitry Controlled by Zcf29

2016 ◽  
pp. AAC.01959-16 ◽  
Author(s):  
Tanvi Shekhar-Guturja ◽  
Walters Aji Tebung ◽  
Harley Mount ◽  
Ningning Liu ◽  
Julia R. Köhler ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcription Factor ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Transcriptional Profiling ◽  
Antifungal Drugs ◽  
Multidrug Efflux ◽  
Tor Signaling ◽  
Transcription Factor Genes ◽  
Life Threatening

Invasive fungal infections are a leading cause of human mortality. Effective treatment is hindered by the rapid emergence of resistance to the limited number of antifungal drugs, demanding new strategies to treat life-threatening fungal infections. Here, we explore a powerful strategy to enhance antifungal efficacy using the natural product beauvericin against leading human fungal pathogens. We found that beauvericin potentiates the activity of azole antifungals against azole-resistantCandidaisolates via inhibition of multidrug efflux, and that beauvericin itself is effluxed via Yor1. As observed inSaccharomyces cerevisiae, we determined that beauvericin inhibits TOR signaling inCandida albicans. To further characterize beauvericin activity inC. albicans, we leveraged genome sequencing of beauvericin-resistant mutants. Resistance was conferred by mutations in transcription factor genesTAC1,which is a key regulator of multidrug efflux, andZCF29, which was uncharacterized. Transcriptional profiling and chromatin immunoprecipitation coupled to microarray analyses revealed that Zcf29 binds to and regulates the expression of multidrug transporter genes. Beyond drug resistance, we also discovered that beauvericin blocks theC. albicansmorphogenetic transition from yeast to filamentous growth in response to diverse cues. We found that beauvericin represses the expression of many filament-specific genes, including the transcription factorBRG1. Thus, we illuminate novel circuitry regulating multidrug efflux, and establish that simultaneously targeting drug resistance and morphogenesis provides a promising strategy to combat life-threatening fungal infections.

scholarly journals A Multidisciplinary Approach to Fungal Infections: One-Year Experiences of a Center of Expertise in Mycology

2020 ◽  
Vol 6 (4) ◽  
pp. 274
Author(s):  
Nico A. F. Janssen ◽  
Roger J. M. Brüggemann ◽  
Monique H. Reijers ◽  
Stefanie S. V. Henriet ◽  
Jaap ten Oever ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Test Results ◽  
Pulmonary Infections ◽  
Multidisciplinary Meetings ◽  
Chronic Pulmonary Aspergillosis ◽  
Center Of Expertise ◽  
Polymerase Chain ◽  
One Year ◽  
Systemic Infections

Invasive fungal diseases (IFDs) often represent complicated infections in complex patient populations. The Center of Expertise in Mycology Radboudumc/CWZ (EMRC) organizes a biweekly multidisciplinary mycology meeting to discuss patients with severe fungal infections and to provide comprehensive advice regarding diagnosis and treatment. Here, we describe the patient population discussed at these meetings during a one-year period with regards to their past medical history, diagnosis, microbiological and other diagnostic test results and antifungal therapy. The majority of patients discussed were adults (83.1%), 62.5% of whom suffered from pulmonary infections or signs/symptoms, 10.9% from otorhinolaryngeal infections and/or oesophagitis, 9.4% from systemic infections and 9.4% from central nervous system infections. Among children, 53.8% had pulmonary infections or signs/symptoms, 23.1% systemic fungal infections and 23.1% other, miscellaneous fungal infections. 52.5% of adult patients with pulmonary infections/symptoms fulfilled diagnostic criteria for chronic pulmonary aspergillosis (CPA). Culture or polymerase chain reaction (PCR) demonstrated fungal pathogens in 81.8% of patients, most commonly Aspergillus. A multidisciplinary mycology meeting can be a useful addition to the care for patients with (I)FDs and can potentially aid in identifying healthcare and research needs regarding the field of fungal infections. The majority of patients discussed at the multidisciplinary meetings suffered from pulmonary infections, predominantly CPA.

Immunology of fungal disease

2017 ◽  
Author(s):  
Ivy M. Dambuza ◽  
Jeanette Wagener ◽  
Gordon D. Brown ◽  
Neil A.R. Gow
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Adaptive Immune System ◽  
Cell Types ◽  
Modern Medicine ◽  
Model Systems ◽  
Cell Responses ◽  
Immune Mediated ◽  
Immunodeficiency Virus ◽  
Life Threatening

Advances in modern medicine, such as organ transplantations and the appearance of HIV (human immunodeficiency virus), have significantly increased the patient cohort at risk of developing chronic superficial and life-threatening invasive fungal infections. To tackle this major healthcare problem, there is an urgent need to understand immunity against fungal infections for the purposes of vaccine design or immune-mediated interventions. In this chapter, we give an overview of the components of the innate and adaptive immune system and how they contribute to host defence against fungi. The various cell types contributing to fungal recognition and the subsequent stimulation of phagocytosis, the activation of inflammatory and B- and T-cell responses, and fungal clearance are discussed using the major fungal pathogens as model systems.

scholarly journals Filamentous Fungal Infections in a Tertiary Care Setting: Epidemiology and Clinical Outcome

2021 ◽  
Vol 7 (1) ◽  
pp. 40
Author(s):  
Miriam Van den Nest ◽  
Gernot Wagner ◽  
Martin Riesenhuber ◽  
Constantin Dolle ◽  
Elisabeth Presterl ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Tertiary Care ◽  
Invasive Fungal Infections ◽  
University Hospital ◽  
European Organization ◽  
Invasive Infections ◽  
Life Threatening ◽  
Frequent Site

Information on the distribution of filamentous fungal pathogens, which cause potential life-threatening invasive infections mostly in immunocompromised persons, is of great importance. The aim of this study was to evaluate the epidemiology and clinical outcome in patients with infections due to filamentous fungi at the University Hospital of Vienna, Austria. We conducted a retrospective observational study and consecutively included patients of any age with filamentous fungal infections between 2009 and 2017. The classification for probable and proven invasive filamentous fungal infections was based on the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC) criteria or the expert opinion of an experienced clinical mycologist. We included 129 patients (median age: 52 years; 47.3% female) with episodes of 101 proven and probable invasive and 35 localized filamentous fungal infections (16 sinus, 14 eye, one ear, and four deep cutaneous). Aspergillus fumigatus alone accounted for 50.3% of the fungi, which was followed by the Mucorales group (13.7%) and Fusarium spp. (8.5%). Diagnosis was mainly based on culture findings. The lung was the most frequent site of infection. The 30-day and 90-day overall mortality of invasive fungal infections was 30.2% and 42.7%, respectively. We observed a high all-cause mortality among patients with invasive filamentous fungal infections. Prospective data collection in a nationwide registry would be necessary to provide important information on surveillance to clinicians and other decision-makers.

Sign in / Sign up

Export Citation Format

Share Document