174 results found
Stone NR, Rhodes J, Fisher MC, et al., 2019, Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis., J Clin Invest, Vol: 129, Pages: 999-1014
BACKGROUND: Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. METHODS: A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS: Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION: Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistanc
Yu L-S, Rodriguez-Manzano J, Malpartida-Cardenas K, et al., 2019, Rapid and Sensitive Detection of Azole-Resistant Aspergillus fumigatus by Tandem Repeat Loop-Mediated Isothermal Amplification., J Mol Diagn, Vol: 21, Pages: 286-295
Invasive fungal infections caused by multiazole-resistant Aspergillus fumigatus are associated with increasing rates of mortality in susceptible patients. Current methods of diagnosing infections caused by multiazole-resistant A. fumigatus are, however, not well suited for use in clinical point-of-care testing or in the field. Loop-mediated isothermal amplification (LAMP) is a widely used method of nucleic acid amplification with rapid and easy-to-use features, making it suitable for use in different resource settings. Here, we developed a LAMP assay to detect a 34 bp tandem repeat, named TR34-LAMP. TR34 is a high-prevalence allele that, in conjunction with the L98H single-nucleotide polymorphism, is associated with the occurrence of multiazole resistance in A. fumigatus in the environment and in patients. This process was validated with both synthetic double-stranded DNA and genomic DNA prepared from azole-resistant isolates of A. fumigatus. Use of our assay resulted in rapid and specific identification of the TR34 allele with high sensitivity, detecting down to 10 genomic copies per reaction within 25 minutes. Fluorescent and colorimetric detections were used for the analysis of 11 clinical isolates as cross validation. These results show that the TR34-LAMP assay has the potential to accelerate the screening of clinical and environmental A. fumigatus to provide a rapid and accurate diagnosis of azole resistance, which current methods struggle to achieve.
Pool ERM, Winston A, Bagkeris E, et al., 2019, High-risk behaviours, and their associations with mental health, adherence to antiretroviral therapy and HIV parameters, in HIV-positive men who have sex with men, HIV MEDICINE, Vol: 20, Pages: 131-136, ISSN: 1464-2662
Abdolrasouli A, Scourfield A, Rhodes J, et al., 2018, High prevalence of triazole resistance in clinical Aspergillus fumigatus isolates in a specialist cardiothoracic centre, INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, Vol: 52, Pages: 637-642, ISSN: 0924-8579
Farrer RA, Ford CB, Rhodes J, et al., 2018, Transcriptional Heterogeneity of Cryptococcus gattii VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways., mSphere, Vol: 3
Cryptococcus gattii is a pathogenic yeast of humans and other animals which causes disease predominantly in immunocompetent hosts. Infection begins when aerosolized yeast or spores enter the body, triggering an immune response, including engulfment by macrophages. To understand the early transcriptional signals in both the yeast and its mammalian host, we performed a time-course dual-transcriptome sequencing (RNA-seq) experiment for four lineages of C. gattii (lineages VGI to IV) interacting with mouse macrophages at 1, 3, and 6 h postinfection. Comparisons of in vitro to ex vivo gene expression levels indicated that lineage VGII is transcriptionally divergent from non-VGII lineages, including differential expression of genes involved in capsule synthesis, capsule attachment, and ergosterol production. Several paralogous genes demonstrated subfunctionalization between lineages, including upregulation of capsule biosynthesis-related gene CAP2 and downregulation of CAP1 in VGIII. Isolates also compensate for lineage-specific gene losses by overexpression of genetically similar paralogs, including overexpression of capsule gene CAS3 in VGIV, which have lost the CAS31 gene. Differential expression of one in five C. gattii genes was detected following coincubation with mouse macrophages; all isolates showed high induction of oxidative-reduction functions and downregulation of capsule attachment genes. We also found that VGII switches expression of two laccase paralogs (from LAC1 to LAC2) during coincubation of macrophages. Finally, we found that mouse macrophages respond to all four lineages of C. gattii by upregulating FosB/Jun/Egr1 regulatory proteins at early time points. This report highlights the evolutionary breadth of expression profiles among the lineages of C. gattii and the diversity of transcriptional responses at this host-pathogen interface.IMPORTANCE The transcriptional profiles of related pathogens and their responses to host-induced stresses underp
Abdolrasouli A, Petrou MA, Park H, et al., 2018, Surveillance for Azole-Resistant Aspergillus fumigatus in a Centralized Diagnostic Mycology Service, London, United Kingdom, 1998-2017, FRONTIERS IN MICROBIOLOGY, Vol: 9, ISSN: 1664-302X
Ghosh PN, Fisher MC, Bates KA, 2018, Diagnosing Emerging Fungal Threats: A One Health Perspective, FRONTIERS IN GENETICS, Vol: 9, ISSN: 1664-8021
Emerging fungal pathogens are a growing threat to global health, ecosystems, food security, and the world economy. Over the last century, environmental change and globalized transport, twinned with the increasing application of antifungal chemical drugs have led to increases in outbreaks of fungal diseases with sometimes catastrophic effects. In order to tackle contemporary epidemics and predemic threats, there is a pressing need for a unified approach in identification and monitoring of fungal pathogens. In this paper, we discuss current high throughput technologies, as well as new platforms capable of combining diverse data types to inform practical epidemiological strategies with a focus on emerging fungal pathogens of wildlife.
Farrer RA, Ford CB, Rhodes J, et al., 2018, Transcriptional Heterogeneity of Cryptococcus gattii VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways, MSPHERE, Vol: 3, ISSN: 2379-5042
Abdolrasouli A, Bercusson AC, Rhodes JL, et al., 2018, Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis, MYCOSES, Vol: 61, Pages: 665-673, ISSN: 0933-7407
Canessa S, Bozzuto C, Campbell Grant EH, et al., 2018, Decision-making for mitigating wildlife diseases: From theory to practice for an emerging fungal pathogen of amphibians, Journal of Applied Ecology, Vol: 55, Pages: 1987-1996, ISSN: 0021-8901
Conservation science can be most effective in its decision-support role when seeking answers to clearly formulated questions of direct management relevance. Emerging wildlife diseases, a driver of global biodiversity loss, illustrate the challenges of performing this role: in spite of considerable research, successful disease mitigation is uncommon. Decision analysis is increasingly advocated to guide mitigation planning, but its application remains rare. Using an integral projection model, we explored potential mitigation actions for avoiding population declines and the ongoing spatial spread of the fungus Batrachochytrium salamandrivorans (Bsal). This fungus has recently caused severe amphibian declines in north-western Europe and currently threatens Palearctic salamander diversity. Available evidence suggests that a Bsal outbreak in a fire salamander (Salamandra salamandra) population will lead to its rapid extirpation. Treatments such as antifungals or probiotics would need to effectively interrupt transmission (reduce probability of infection by nearly 90%) in order to reduce the risk of host extirpation and successfully eradicate the pathogen. Improving the survival of infected hosts is most likely to be detrimental as it increases the potential for pathogen transmission and spread. Active removal of a large proportion of the host population has some potential to locally eradicate Bsal and interrupt its spread, depending on the presence of Bsal reservoirs and on the host's spatial dynamics, which should therefore represent research priorities. Synthesis and applications. Mitigation of Batrachochytrium salamandrivorans epidemics in susceptible host species is highly challenging, requiring effective interruption of transmission and radical removal of host individuals. More generally, our study illustrates the advantages of framing conservation science directly in the management decision context, rather than adapting to it a posteriori.
Fisher MC, 2018, Epidemiological definitions, terminology and classifications with reference to fungal infections of animals, Emerging and Epizootic Fungal Infections in Animals, Pages: 17-27, ISBN: 9783319720913
© Springer International Publishing AG, part of Springer Nature 2018. Emerging infections caused by fungi have become a widely recognised global phenomenon in animal species and populations worldwide. This chapter details the vocabulary and grammar that is used to discuss such infections. Much of this terminology is specific to the field of mycology, and careful usage is required in the scientific literature and discussion in order to maintain clarity of expression.
© Springer International Publishing AG, part of Springer Nature 2018. The amphibian fungal disease chytridiomycosis is considered one of the greatest threats to biodiversity. This lethal skin disease is caused by chytridiomycete fungi belonging to the genus Batrachochytrium. Although sudden amphibian population declines had occurred since the 1970s in the Americas and Australia, mass mortalities were not observed until the 1990s. The fungus Batrachochytrium dendrobatidis (Bd) was identified as the cause of these declines. It is estimated that Bd has caused the rapid decline or extinction of at least 200 amphibian species, which is probably an underestimation due to the cryptic behaviour of many amphibians such as many salamanders and also the lack of monitoring. A second chytrid species, B. salamandrivorans (Bsal), has recently emerged and caused mass mortality in salamanders in Belgium, the Netherlands and Germany, affecting most salamander and newt taxa in the amphibian community and is considered a major threat to the western Palearctic amphibian biodiversity. In this chapter we review the epidemiology, host pathogen interactions and mitigation strategies of both chytrid pathogens.
Cremin I, Watson O, Heffernan A, et al., 2018, An infectious way to teach students about outbreaks, EPIDEMICS, Vol: 23, Pages: 42-48, ISSN: 1755-4365
Thorpe CJ, Lewis TR, Fisher MC, et al., 2018, Climate structuring of Batrachochytrium dendrobatidis infection in the threatened amphibians of the northern Western Ghats, India, ROYAL SOCIETY OPEN SCIENCE, Vol: 5, ISSN: 2054-5703
Rhodes J, Abdolrasouli A, Farrer RA, et al., 2018, Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris (vol 7, pg 43, 2018), EMERGING MICROBES & INFECTIONS, Vol: 7, ISSN: 2222-1751
Fisher MC, Hawkins NJ, Sanglard D, et al., 2018, Worldwide emergence of resistance to antifungal drugs challenges human health and food security, Science, Vol: 360, Pages: 739-742, ISSN: 0036-8075
The recent rate of emergence of pathogenic fungi that are resistant to the limited number of commonly used antifungal agents is unprecedented. The azoles, for example, are used not only for human and animal health care and crop protection but also in antifouling coatings and timber preservation. The ubiquity and multiple uses of azoles have hastened the independent evolution of resistance in many environments. One consequence is an increasing risk in human health care from naturally occurring opportunistic fungal pathogens that have acquired resistance to this broad class of chemicals. To avoid a global collapse in our ability to control fungal infections and to avoid critical failures in medicine and food security, we must improve our stewardship of extant chemicals, promote new antifungal discovery, and leverage emerging technologies for alternative solutions.
Fisher MC, Ghosh P, Shelton JMG, et al., 2018, Development and worldwide use of non-lethal, and minimal population-level impact, protocols for the isolation of amphibian chytrid fungi, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
O'Hanlon SJ, Rieux A, Farrer RA, et al., 2018, Recent Asian origin of chytrid fungi causing global amphibian declines, SCIENCE, Vol: 360, Pages: 621-+, ISSN: 0036-8075
Dambuza IM, Drake T, Chapuis A, et al., 2018, The Cryptococcus neoformans Titan cell is an inducible and regulated morphotype underlying pathogenesis, PLOS PATHOGENS, Vol: 14, ISSN: 1553-7366
Colley T, Sehra G, Chowdhary A, et al., 2018, In vitro and in vivo efficacy of a novel and long acting fungicidal azole, PC1244 on Aspergillus fumigatus infection, Antimicrobial Agents and Chemotherapy, Vol: 62, ISSN: 0066-4804
The antifungal effects of the novel triazole, PC1244, designed for topical or inhaled administration, againstA. fumigatushave been tested in a range ofin vitroandin vivostudies. PC1244 demonstrated potent antifungal activities against clinicalA. fumigatusisolates (N=96) with a MIC range of 0.016--0.25 μg/ml, whereas the MIC range for voriconazole was 0.25--0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinantA. fumigatusCYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis inA. fumigatuswith an IC50of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC ranged from <0.0078∼2 μg/ml), especially onAspergillus terreus,Trichophyton rubrum,Candida albicans,Candida glabrata,Candida krusei,Cryptococcus gattii,Cryptococcus neoformans and Rhizopus oryzaePC1244 also proved to be quickly absorbed into bothA. fumigatushyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (MFC, 2 μg/ml), which was 8-fold more potent than voriconazole.In vivo, once daily intranasal administration of PC1244 (3.2 ∼ 80μg/mL) to temporarily neutropenic, immunocompromised mice 24h after inoculation with itraconazole-susceptibleA. fumigatussubstantially reduced fungal load in the lung, galactomannan in serum and circulating inflammatory cytokines. Furthermore, 7 days extended prophylaxis with PC1244 showed superiorin vivoeffects when compared against 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment ofA. fumigatusinfection in the lungs of humans.
Rhodes J, Fisher MC, 2018, Breaching Pathogeographic Barriers by the Bat White-Nose Fungus, MBIO, Vol: 9, ISSN: 2150-7511
Valenzuela-Sanchez A, O'Hanlon SJ, Alvarado-Rybak M, et al., 2018, Genomic epidemiology of the emerging pathogen Batrachochytrium dendrobatidis from native and invasive amphibian species in Chile, TRANSBOUNDARY AND EMERGING DISEASES, Vol: 65, Pages: 309-314, ISSN: 1865-1674
Rhodes J, Abdolrasouli A, Farrer RA, et al., 2018, Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris, EMERGING MICROBES & INFECTIONS, Vol: 7, ISSN: 2222-1751
Bates KA, Clare FC, O'Hanlon S, et al., 2018, Amphibian chytridiomycosis outbreak dynamics are linked with host skin bacterial community structure, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
Fisher M, Ghosh P, Shelton J, et al., 2018, Development and worldwide use of a non-lethal and minimal population-level impact protocols for the isolation of chytrids from amphibians
Parasitic chytrid fungi have emerged as a significant threat to amphibian species worldwide, necessitating the development of techniques to isolate these pathogens into sterile culture for research purposes. However, early methods of isolating chytrids from their hosts relied on killing amphibians. We modified a pre-existing protocol for isolating chytrids from infected animals to use toe clips and biopsies from toe webbing rather than euthanizing hosts, and distributed the protocol to interested researchers worldwide as part of the BiodivERsA project RACE; here called the RML protocol. In tandem, we developed a lethal procedure for isolating chytrids from tadpole mouthparts. Reviewing a database of use a decade after their inception, we find that these methods have been widely applied across at least 5 continents, 23 countries and in 62 amphibian species, and have been successfully used to isolate chytrids in remote field locations. Isolation of chytrids by the non-lethal RML protocol occured in 18% of attempts with 207 fungal isolates and three species of chytrid being recovered. Isolation of chytrids from tadpoles occured in 43% of attempts with 334 fungal isolates of one species (Batrachochytrium dendrobatidis) being recovered. Together, these methods have resulted in a significant reduction and refinement of our use of threatened amphibian species and have improved our ability to work with this important group of emerging fungal pathogens.
Fernandez-Loras A, Fernandez-Beaskoetxea S, Arriero E, et al., 2017, Early exposure to Batrachochytrium dendrobatidis causes profound immunosuppression in amphibians, EUROPEAN JOURNAL OF WILDLIFE RESEARCH, Vol: 63, ISSN: 1612-4642
Rhodes J, Abdolrasouli A, Farrer R, et al., 2017, Rapid genome sequencing for outbreak analysis of the emerging human fungal pathogen Candida auris
Background: Candida auris was first described in 2009, and has since caused nosocomial outbreaks, invasive infections and fungaemia across 11 countries in five continents. An outbreak of C. auris occurred in a specialised cardiothoracic London hospital between April 2015 and November 2016, which to date has been the largest outbreak reported worldwide, involving a total of 72 patients. Methods: To understand the epidemiology of C. auris infection within this hospital, we sequenced the genomes of outbreak isolates using Oxford Nanopore Technologies and Illumina in order to type antifungal resistance alleles and to explore the outbreak within its local and global context. Findings: Phylogenomic analysis placed the UK outbreak in the India/Pakistan clade, demonstrating an Asian origin. The outbreak showed similar diversity to that of the entire clade and limited local spatiotemporal clustering was observed. One isolate displayed resistance to both echinocandins and 5-flucytosine; the former was associated with a serine to tyrosine amino acid substitution in the gene FKS1, and the latter was associated with a phenylalanine to isoleucine substitution in the gene FUR1. These mutations are novel for this pathogen. Interpretation: Multiple differential episodic selection of antifungal resistant genotypes has occurred within a genetically heterogenous population across this outbreak, creating a resilient pathogen and making it difficult to define local-scale patterns of transmission as well as implementing outbreak control measures. Funding: Antimicrobial Research Collaborative, Imperial College London
Chow NA, Gade L, Lockhart S, et al., 2017, Using whole-genome sequencing to elucidate the epidemiology of the globally emerging, multidrug-resistant yeast Candida auris, Publisher: WILEY, Pages: 21-21, ISSN: 0933-7407
Rhodes J, Desjardins CA, Sykes SM, et al., 2017, Tracing Genetic Exchange and Biogeography of Cryptococcus neoformans var. grubii at the Global Population Level, GENETICS, Vol: 207, Pages: 327-346, ISSN: 0016-6731
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