scholarly journals A Novel Virulence Phenotype Rapidly AssessesCandidaFungal Pathogenesis in Healthy and ImmunocompromisedCaenorhabditis elegansHosts

mSphere ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Dorian J. Feistel ◽  
Rema Elmostafa ◽  
Nancy Nguyen ◽  
McKenna Penley ◽  
Levi Morran ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Immune Function ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Opportunistic Pathogens ◽  
Pathogenic Potential ◽  
Content Type ◽  
Host Fitness ◽  
Pathogen Virulence ◽  
Delayed Reproduction

ABSTRACTThe yeastCandida albicansis an opportunistic pathogen of humans, meaning that despite commensal interactions with its host, it can transition to a harmful pathogen. WhileC. albicansis the predominant species isolated in the human gastrointestinal mycobiome and is implicated in fungal infection, infections due to non-albicansCandidaspecies are rapidly rising. Studying the factors that contribute to virulence is often challenging and frequently depends on many contexts, including host immune status and pathogen genetic background. Here, we utilize the nematodeCaenorhabditis elegansas a perspicuous and efficient model host system to study fungal infections ofCandidapathogens. We find that, in addition to reducing lifetime host survival, exposure toC. albicansresults in delayed reproduction, which significantly reduced lineage growth over multiple generations. Furthermore, we assessed fungal pathogen virulence inC. eleganshosts compromised for innate immune function and detected increased early mortality, reduced brood sizes, and delayed reproduction relative to infected healthy hosts. Importantly, by assessing virulence in both healthy and immunocompromised host backgrounds, we reveal the pathogen potential in non-albicansCandidaspecies. Taken together, we present a novel lineage growth assay to measure reduction in host fitness associated with fungal infection and demonstrate significant interactions between pathogen and host immune function that contribute to virulence.IMPORTANCEOpportunistic pathogens are commensals capable of causing disease and are serious threats to human health. It is critical to understand the mechanisms and host contexts under which opportunistic pathogens become virulent. In this work, we present a novel assay to quickly and quantitatively measure pathogen virulence in healthy and immunocompromised nematode hosts. We found thatCandidaspecies, one of the most prominent fungal opportunistic pathogens of humans, decrease host fitness by reducing survival and impacting host reproduction. Most importantly, by measuring virulence in hosts that have intact or compromised immune function, we can reveal the pathogenic potential of opportunistic fungal pathogens.

scholarly journals A novel virulence phenotype rapidly assesses Candida fungal pathogenesis in healthy and immunocompromised Caenorhabditis elegans hosts

2018 ◽  
Author(s):  
Dorian J. Feistel ◽  
Rema Elmostafa ◽  
Nancy Nguyen ◽  
McKenna Penley ◽  
Levi Morran ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Fungal Infection ◽  
Immune Function ◽  
Fungal Infections ◽  
Immunocompromised Host ◽  
Opportunistic Pathogen ◽  
C Elegans ◽  
Pathogen Virulence ◽  
Delayed Reproduction ◽  
Growth Assay

AbstractThe yeast Candida albicans is an opportunistic pathogen of humans, meaning that despite commensal interactions with its host, it can transition to a harmful pathogen. While C. albicans is the predominant species isolated in the human mycobiome and implicated in fungal infection, infections due to non-albicans Candida species are rapidly rising. Studying the factors that contribute to virulence is often challenging and frequently depends on many contexts including host immune status and pathogen genetic background. Here, we utilize the nematode Caenorhabditis elegans as a perspicuous and efficient model host system to study fungal infections of Candida pathogens. We find that in addition to reducing lifetime host survival, exposure to C. albicans results in delayed reproduction, which significantly reduced lineage growth over multiple generations. Furthermore, we assessed fungal pathogen virulence in C. elegans hosts compromised for innate immune function and detected increased early mortality, reduced brood sizes and delayed reproduction relative to infected healthy hosts. Importantly, by assessing virulence in both healthy and immunocompromised host backgrounds we reveal the pathogen potential in non-albicans Candida species. Taken together, we present a novel lineage growth assay to measure reduction in host fitness associated with fungal infection and demonstrate significant interactions between pathogen and host immune function that contribute to virulence.

scholarly journals Estimated Burden of Fungal Infections in Oman

2020 ◽  
Vol 7 (1) ◽  
pp. 5
Author(s):  
Abdullah M. S. Al-Hatmi ◽  
Mohammed A. Al-Shuhoumi ◽  
David W. Denning
Keyword(s):  
Fungal Infection ◽  
Fungal Infections ◽  
Epidemiological Studies ◽  
Vaginal Candidiasis ◽  
Skin Infections ◽  
Opportunistic Pathogens ◽  
Fungal Rhinosinusitis ◽  
Populations At Risk ◽  
Different Populations ◽  
Underlying Pathology

For many years, fungi have emerged as significant and frequent opportunistic pathogens and nosocomial infections in many different populations at risk. Fungal infections include disease that varies from superficial to disseminated infections which are often fatal. No fungal disease is reportable in Oman. Many cases are admitted with underlying pathology, and fungal infection is often not documented. The burden of fungal infections in Oman is still unknown. Using disease frequencies from heterogeneous and robust data sources, we provide an estimation of the incidence and prevalence of Oman’s fungal diseases. An estimated 79,520 people in Oman are affected by a serious fungal infection each year, 1.7% of the population, not including fungal skin infections, chronic fungal rhinosinusitis or otitis externa. These figures are dominated by vaginal candidiasis, followed by allergic respiratory disease (fungal asthma). An estimated 244 patients develop invasive aspergillosis and at least 230 candidemia annually (5.4 and 5.0 per 100,000). Only culture and microscopy are currently available for diagnosis, so case detection is suboptimal. Uncertainty surrounds these figures that trigger the need for urgent local epidemiological studies with more sensitive diagnostics.

Fungal Infection in Cystic Fibrosis

2021 ◽  
Vol 17 (2) ◽  
pp. 118-124
Author(s):  
Amirmehdi Sarvestani ◽  
Mohammad Almasian ◽  
Amirhossein Nafari
Keyword(s):  
Cystic Fibrosis ◽  
Fungal Infection ◽  
Fungal Pathogens ◽  
Respiratory Infections ◽  
Fungal Infections ◽  
Genetic Disorder ◽  
Medical Science ◽  
Resistant Species ◽  
Online Databases ◽  
New Treatments

Background: The prevalence of fungal infections has been increasing in recent years. Cystic fibrosis (CF) is a genetic disorder that affects organs such as the intestines, liver, pancreas, and especially the lungs. Introduction: Fungal pathogens are becoming a challenge in CF. Advanced medical science is associated with longer life expectancy in some patient groups. Method: A review was conducted on studies found on online databases, including Google Scholar, PubMed, and Scopus. Internet-based searches were performed on these databases for cystic fibrosis, respiratory infections, and fungal infection profiling to identify all relevant studies published between 2010 and 2020. Result: Fungal pathogens most frequently isolated from the respiratory tract include the Aspergillus genus, the Candida genus, Scedosporium apiospermum, and the Rasamsonia genus. In cystic fibrosis, these organisms usually colonize the respiratory and intestinal tracts and cause hypersensitivity responses and invasive diseases. Conclusion: Fungus-patient interactions are complicated and depend on various factors. Moreover, the emergence of drug-resistant species is a serious health issue, and the development of new treatments is crucial.

Identification and in Vitro Susceptibility Pattern of Fungal Pathogens in Immunocompromised Patients with invasive Fungal Infections

2021 ◽  
Vol 30 (3) ◽  
pp. 127-134
Author(s):  
Shaimaa A.S. Selem ◽  
Neveen A. Hassan ◽  
Mohamed Z. Abd El-Rahman ◽  
Doaa M. Abd El-Kareem
Keyword(s):  
Intensive Care ◽  
Fungal Infection ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Invasive Fungal Infections ◽  
Immunocompromised Patients ◽  
University Hospitals ◽  
Vitek 2

Background: In intensive care units, invasive fungal infections have become more common, particularly among immunocompromised patients. Early identification and starting the treatment of those patients with antifungal therapy is critical for preventing unnecessary use of toxic antifungal agents. Objective: The aim of this research is to determine which common fungi cause invasive fungal infection in immunocompromised patients, as well as their antifungal susceptibility patterns in vitro, in Assiut University Hospitals. Methodology: This was a hospital based descriptive study conducted on 120 patients with clinical suspicion of having fungal infections admitted at different Intensive Care Units (ICUs) at Assiut University Hospitals. Direct microscopic examination and inoculation on Sabouraud Dextrose Agar (SDA) were performed on the collected specimens. Isolated yeasts were classified using phenotypic methods such as chromogenic media (Brilliance Candida agar), germ tube examination, and the Vitek 2 system for certain isolates, while the identification of mould isolates was primarily based on macroscopic and microscopic characteristics. Moulds were tested in vitro for antifungal susceptibility using the disc diffusion, and yeast were tested using Vitek 2 device cards. Results: In this study, 100 out of 120 (83.3%) of the samples were positive for fungal infection. Candida and Aspergillus species were the most commonly isolated fungal pathogens. The isolates had the highest sensitivity to Amphotericin B (95 %), followed by Micafungin (94 %) in an in vitro sensitivity survey. Conclusion: Invasive fungal infections are a leading cause of morbidity and mortality in immunocompromised patients, with Candida albicans being the most frequently isolated yeast from various clinical specimens; however, the rise in resistance, especially to azoles, is a major concern.

scholarly journals Fungal Infection in Lung Transplantation

2021 ◽  
Vol 42 (03) ◽  
pp. 471-482
Author(s):  
Cassie C. Kennedy ◽  
Kelly M. Pennington ◽  
Elena Beam ◽  
Raymund R. Razonable
Keyword(s):  
Fungal Infection ◽  
Fungal Pathogens ◽  
Lung Transplant ◽  
Fungal Infections ◽  
Treatment Strategies ◽  
Invasive Fungal Infections ◽  
Molecular Diagnostic ◽  
Candida Spp ◽  
Diagnostic Strategies ◽  
Culture Techniques

AbstractInvasive fungal infections threaten lung transplant outcomes with high associated morbidity and mortality. Pharmacologic prophylaxis may be key to prevent posttransplant invasive fungal infections, but cost, adverse effects, and absorption issues are barriers to effective prophylaxis. Trends in fungal infection diagnostic strategies utilize molecular diagnostic methodologies to complement traditional histopathology and culture techniques. While lung transplant recipients are susceptible to a variety of fungal pathogens, Candida spp. and Aspergillus spp. infections remain the most common. With emerging resistant organisms and multiple novel antifungal agents in the research pipeline, it is likely that treatment strategies will continue to evolve.

scholarly journals A Heat-Killed Cryptococcus Mutant Strain Induces Host Protection against Multiple Invasive Mycoses in a Murine Vaccine Model

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Yina Wang ◽  
Keyi Wang ◽  
Jorge A. Masso-Silva ◽  
Amariliz Rivera ◽  
Chaoyang Xue
Keyword(s):  
Immune Deficiency ◽  
T Cells ◽  
Fungal Pathogens ◽  
Vaccine Candidate ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Host Immunity ◽  
Content Type ◽  
A Subunit ◽  
F Box Protein

ABSTRACT Cryptococcus neoformans is a fungal pathogen that infects the lungs and then often disseminates to the central nervous system, causing meningitis. How Cryptococcus is able to suppress host immunity and escape the antifungal activity of macrophages remains incompletely understood. We reported that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase, promotes Cryptococcus virulence by regulating host-Cryptococcus interactions. Our recent studies demonstrated that the fbp1Δ mutant elicited superior protective Th1 host immunity in the lungs and that the enhanced immunogenicity of heat-killed fbp1Δ yeast cells can be harnessed to confer protection against a subsequent infection with the virulent parental strain. We therefore examined the use of heat-killed fbp1Δ cells in several vaccination strategies. Interestingly, the vaccine protection remains effective even in mice depleted of CD4+ T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that vaccinating mice with heat-killed fbp1Δ induces significant cross-protection against challenge with diverse invasive fungal pathogens, including C. neoformans, C. gattii, and Aspergillus fumigatus, as well as partial protection against Candida albicans. Thus, our data suggest that the heat-killed fbp1Δ strain has the potential to be a suitable vaccine candidate against cryptococcosis and other invasive fungal infections in both immunocompetent and immunocompromised populations. IMPORTANCE Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans, elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed fbp1Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4+ T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations.

Opportunistic Fungal Infection

Chest Imaging ◽  
2019 ◽  
pp. 209-213
Author(s):  
Sonia L. Betancourt
Keyword(s):  
Fungal Infection ◽  
Opportunistic Infection ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Hematologic Malignancy ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Candida Spp ◽  
Common Opportunistic Infection ◽  
Cryptococcus Spp

Opportunistic fungal infections are caused by fungi that are nonpathogenic in the immunocompetent host, many of which are part of the normal upper respiratory tract flora. These organisms may cause pulmonary infection in immunocompromised hosts. Immunocompromised patients and patients with febrile neutropenia with opportunistic fungal infections may have normal chest radiographs. Thus, chest CT should be performed for further evaluation. Imaging abnormalities in this patient population should raise suspicion for opportunistic infection. Neutropenia is the single most important risk factor for Aspergillosis. Aspergillus is the most common opportunistic infection in patients with hematologic malignancy and bone marrow transplantation. Aspergillus spp., Candida spp., and Cryptococcus spp. are the most common fungal infections in patients with solid organ transplantation. Pneumocystis jirovecii is the most common fungal infection in patients AIDS with CD4 count s<200 cells/mm3. Cryptococcal pneumonia is also common in this population. There has been a recent increase in uncommon fungal pathogens causing invasive pulmonary disease.

scholarly journals Crystal Structures of Full-Length Lanosterol 14α-Demethylases of Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide Tools for Antifungal Discovery

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Mikhail V. Keniya ◽  
Manya Sabherwal ◽  
Rajni K. Wilson ◽  
Matthew A. Woods ◽  
Alia A. Sagatova ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Crystal Structures ◽  
Candida Glabrata ◽  
Fungal Pathogens ◽  
Catalytic Domain ◽  
Fungal Infections ◽  
Binding Pocket ◽  
Full Length ◽  
Content Type ◽  
Cure Rates

ABSTRACT Targeting lanosterol 14α-demethylase (LDM) with azole drugs provides prophylaxis and treatments for superficial and disseminated fungal infections, but cure rates are not optimal for immunocompromised patients and individuals with comorbidities. The efficacy of azole drugs has also been reduced due to the emergence of drug-resistant fungal pathogens. We have addressed the need to improve the potency, spectrum, and specificity for azoles by expressing in Saccharomyces cerevisiae functional, recombinant, hexahistidine-tagged, full-length Candida albicans LDM (CaLDM6×His) and Candida glabrata LDM (CgLDM6×His) and determining their X-ray crystal structures. The crystal structures of CaLDM6×His, CgLDM6×His, and ScLDM6×His have the same fold and bind itraconazole in nearly identical conformations. The catalytic domains of the full-length LDMs have the same fold as the CaLDM6×His catalytic domain in complex with posaconazole, with minor structural differences within the ligand binding pocket. Our structures give insight into the LDM reaction mechanism and phenotypes of single-site CaLDM mutations. This study provides a practical basis for the structure-directed discovery of novel antifungals that target LDMs of fungal pathogens.

scholarly journals Toxoflavin Produced byBurkholderia gladiolifromLycoris aureaIs a New Broad-Spectrum Fungicide

2019 ◽  
Vol 85 (9) ◽  
Author(s):  
Xiaodan Li ◽  
Yikui Li ◽  
Ren Wang ◽  
Qizhi Wang ◽  
Ling Lu
Keyword(s):  
Antifungal Activity ◽  
Broad Spectrum ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Endophytic Bacterium ◽  
Content Type ◽  
Burkholderia Gladioli ◽  
Lycoris Aurea ◽  
Resistant Mutants

ABSTRACTFungal infections not only cause extensive agricultural damage but also result in serious diseases in the immunodeficient populations of human beings. Moreover, the increasing emergence of drug resistance has led to a decrease in the efficacy of current antifungals. Thus, screening of new antifungal agents is imperative in the fight against antifungal drug resistance. In this study, we show that an endophytic bacterium,Burkholderia gladioliHDXY-02, isolated from the medicinal plantLycoris aurea, showed broad-spectrum antifungal activity against plant and human fungal pathogens. An antifungal ability assay indicated that the bioactive component was produced from strain HDXY-02 having an extracellular secreted component with a molecular weight lower than 1,000 Da. In addition, we found that this new antifungal could be produced effectively by liquid fermentation of HDXY-02. Furthermore, the purified component contributing to the antifungal activity was identified to be toxoflavin, a yellow compound possessing a pyrimido[5,4-e][1,2,4]triazine ring.In vitrobioactivity studies demonstrated that purified toxoflavin fromB. gladioliHDXY-02 cultures had a significant antifungal activity against the human fungal pathogenAspergillus fumigatus, resulting in abolished germination of conidia. More importantly, the growth inhibition by toxoflavin was observed in both wild-type and drug-resistant mutants (cyp51Aand non-cyp51A) ofA. fumigatus. Finally, an optimized protocol for the large-scale production of toxoflavin (1,533 mg/liter) has been developed. Taken together, our findings provide a promising biosynthetic resource for producing a new antifungal reagent, toxoflavin, from isolates of the endophytic bacteriumB. gladioli.IMPORTANCEHuman fungal infections are a growing problem associated with increased morbidity and mortality. Moreover, a growing number of antifungal-resistant fungal isolates have been reported over the past decade. Thus, the need for novel antifungal agents is imperative. In this study, we show that an endophytic bacterium,Burkholderia gladioli, isolated from the medicinal plantLycoris aurea, is able to abundantly secrete a compound, toxoflavin, which has a strong fungicidal activity not only against plant fungal pathogens but also against human fungal pathogensAspergillus fumigatusandCandida albicans,Cryptococcus neoformans, and the model filamentous fungusAspergillus nidulans. More importantly, toxoflavin also displays an efficacious inhibitory effect against azole antifungal-resistant mutants ofA. fumigatus. Consequently, our findings provide a promising approach to abundantly produce toxoflavin, which has novel broad-spectrum antifungal activity, especially against those currently problematic drug-resistant isolates.

scholarly journals A CRISPR Interference Platform for Efficient Genetic Repression in Candida albicans

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Lauren Wensing ◽  
Jehoshua Sharma ◽  
Deeva Uthayakumar ◽  
Yannic Proteau ◽  
Alejandro Chavez ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Human Disease ◽  
Transcriptional Repression ◽  
Fungal Pathogen ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Content Type ◽  
Guide Rna ◽  
Crispr Interference ◽  
Functional Genomic Analysis

ABSTRACT Fungal pathogens are emerging as an important cause of human disease, and Candida albicans is among the most common causative agents of fungal infections. Studying this fungal pathogen is of the utmost importance and necessitates the development of molecular technologies to perform comprehensive genetic and functional genomic analysis. Here, we designed and developed a novel clustered regularly interspaced short palindromic repeat interference (CRISPRi) system for targeted genetic repression in C. albicans. We engineered a nuclease-dead Cas9 (dCas9) construct that, paired with a guide RNA targeted to the promoter of an endogenous gene, is capable of targeting that gene for transcriptional repression. We further optimized a favorable promoter locus to achieve repression and demonstrated that fusion of dCas9 to an Mxi1 repressor domain was able to further enhance transcriptional repression. Finally, we demonstrated the application of this CRISPRi system through genetic repression of the essential molecular chaperone HSP90. This is the first demonstration of a functional CRISPRi repression system in C. albicans, and this valuable technology will enable many future applications in this critical fungal pathogen. IMPORTANCE 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.

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