Investigating Fungal Outbreaks in the 21st Century

Litvintseva, Anastasia P.; Brandt, Mary E.; Mody, Rajal K.; Lockhart, Shawn R.

doi:10.1371/journal.ppat.1004804

Cited by 27 publications

(22 citation statements)

References 21 publications

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“…In contrast, the B. hawaiiensis isolates implicated in the 2012 endophthalmitis outbreak were clonal to the extent that was shown with this typing system, which confirms the epidemiological data suggesting that the mode of transmission was likely due to contaminated triamcinolone steroid injected into the eyes of patients (5). Although fungal outbreaks are relatively uncommon, there have been a number of high-profile fungal-related outbreaks in recent years (27). Fungal typing systems were not available for the majority of these clusters, and typing was performed in most cases after the epidemiologic investigation was completed.…”

Section: Discussionsupporting

confidence: 79%

Development of a Multilocus Sequence Typing System for Medically Relevant Bipolaris Species

et al. 2015

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cMultilocus sequence typing (MLST) is the gold standard genotyping technique for many microorganisms. This classification approach satisfies the requirements for a high-resolution, standardized, and archivable taxonomic system. Here, we describe the development of a novel MLST system to assist with the investigation of an unusual cluster of surgical site infections caused by Bipolaris spp. in postoperative cardiothoracic surgery (POCS) patients during January 2008 to December 2013 in the southeastern United States. We also used the same MLST system to perform a retrospective analysis on isolates from a 2012 Bipolaris endophthalmitis outbreak caused by a contaminated product. This MLST system showed high intraspecies discriminatory power for Bipolaris spicifera, B. hawaiiensis, and B. australiensis. Based on the relatedness of the isolates, the MLST data supported the hypothesis that infections in the POCS cluster were from different environmental sources while confirming that the endophthalmitis outbreak resulted from a point source, which was a contaminated medication. Dematiaceous fungi belonging to the genus Bipolaris are abundant in the environment. Many species in this genus are known to cause devastating disease in plants and staple crops around the world (1). In humans, they are common etiological agents of fungal sinusitis. Surgical site infections (SSIs) and deep tissue and invasive infections by members of this genus do occur, but they are extremely rare and typically associated with immunocompromised patients (2-7). The common disease-causing Bipolaris species in humans are Bipolaris spicifera, B. hawaiiensis, and, occasionally, B. australiensis (3). A recent proposal transfers these species to the genus Curvularia (1), but this new name has not yet been widely accepted.In the clinical setting, Bipolaris infections are usually diagnosed using microscopy to distinguish the morphological characteristics of the fungus following culture. In recent years, the sequence comprising the internal transcribed spacer (ITS) regions and the 5.8S nuclear rRNA genes of the ribosomal cistron has been exploited for species assignment of dematiaceous fungi (8, 9). In most cases, ITS-based sequence identification is sufficient for determining species. However, ITS-based sequencing is limited by its dependence on the completeness and accuracy of available DNA sequence databases. A DNA typing system employing two or more loci, such as multilocus sequence typing (MLST), can be used when it is necessary to distinguish between isolates within a species (10, 11). MLST has been successfully implemented for species identification within a species complex as well as strain differentiation within a species for various fungal pathogens of humans such as Aspergillus fumigatus, Candida albicans, Candida glabrata, Candida tropicalis, Cryptococcus gattii, Cryptococcus neoformans, and Fusarium sp. (12-18). The recent investigations of infections caused by dematiaceous fungi (5, 19) have highlighted the importance of high-resolution, sta...

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Section: Discussionsupporting

confidence: 79%

Development of a Multilocus Sequence Typing System for Medically Relevant Bipolaris Species

et al. 2015

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“…Investigating the ecology and distribution of genotypes within and among populations of a pathogen is important for monitoring outbreaks, determining variance in virulence, and predicting disease progression ( 37 ). Correlating disease severity with pathogen genotype by using genome-wide association studies might assist in identifying genetic-based differences in virulence ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Use of Population Genetics to Assess the Ecology, Evolution, and Population Structure ofCoccidioides

Teixeira¹,

Barker²

2016

Emerg. Infect. Dis.

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“…The search for novel antifungal therapies is an ongoing battle in medical mycology, especially with the growing number of fungal outbreaks and emerging drug resistance issues (33, 34). The latest class of antifungals approved by the FDA are the echinocandins, and Cryptococcus is intrinsically resistant to this class of antifungals (9, 14, 15, 36).…”

Section: Discussionmentioning

confidence: 99%

Puf4 Mediates Post-transcriptional Regulation of Caspofungin Resistance inCryptococcus neoformans

Kalem

Subbiah

Leipheimer

et al. 2020

Preprint

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24Echinocandins have been on the market for 20 years, yet they are the newest class of 25 antifungal drugs. The human fungal pathogen Cryptococcus neoformans is intrinsically resistant 26 to the echinocandin antifungal drug caspofungin, which targets the b-1,3-glucan synthase 27 encoded by the FKS1. Analysis of a C. neoformans puf4∆ mutant, lacking the pumilio/FBF RNA 28 binding protein family member Puf4, revealed exacerbated caspofungin resistance. In contrast, 29 overexpression of PUF4 resulted in caspofungin sensitivity. The FKS1 mRNA contains three 30 Puf4-binding elements (PBEs) in its 5' untranslated region. Puf4 binds with specificity to this 31 region of the FKS1. The FKS1 mRNA was destabilized in the puf4∆ mutant, and the abundance 32 of the FKS1 mRNA was reduced compared to wild type, suggesting that Puf4 is a positive 33 regulator FKS1 mRNA stability. In addition to FKS1, the abundance of additional cell wall 34 biosynthesis genes, including chitin synthases (CHS3, CHS4, CHS6) and deacetylases (CDA1, 35 CDA2, CDA3) as well as a b-1,6-glucan synthase gene (SKN1) was regulated by Puf4 during a 36 caspofungin time course. The use of fluorescent dyes to quantify cell wall components revealed 37 that the puf4∆ mutant had increased chitin content, suggesting a cell wall composition that is 38 less reliant on b-1,3-glucan. Overall, our findings suggest a mechanism by which caspofungin 39 resistance, and more broadly, cell wall biogenesis, is regulated post-transcriptionally by Puf4. 40 41 Importance 42 Cryptococcus neoformans is an environmental fungus that causes pulmonary and central 43 nervous system infections. It is also responsible for 15% of AIDS-related deaths. A major 44 contributor to the high morbidity and mortality statistics is the lack of safe and effective 45 antifungal therapies, especially in resource-poor settings. Yet, antifungal drug development has 46 stalled in the pharmaceutical industry. Therefore, it is of importance to understand the mechanism by which C. neoformans is resistant to caspofungin in order to design adjunctive 48 therapies to potentiate its activity toward this important pathogen. 50 Introduction 51Invasive deep mycoses primarily impact immunocompromised populations causing high rates of 52 morbidity and mortality (1, 2). The pathogenic fungus Cryptococcus neoformans is the causative 53 agent of fatal meningitis most often in patients with defects in cell mediated immunity, including 54 transplant recipients and those living with HIV/AIDS (3-6). C. neoformans is responsible of the 55 15% of AIDS-related deaths (6). Treatment of cryptococcosis is difficult and therapeutic options 56 are limited. Even the best combination treatment using Amphotericin B with 5-fluorocytosine (5-57 FC) is not well tolerated, and 5-FC is often unavailable in resource-poor areas (7). Some of the 58 largest clinal challenges to invasive fungal infections are poor efficacy of the drugs, emerging 59 resistance issues, narrow selection and availability of antifungals especially in the areas where...

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Investigating Fungal Outbreaks in the 21st Century

Cited by 27 publications

References 21 publications

Development of a Multilocus Sequence Typing System for Medically Relevant Bipolaris Species

Development of a Multilocus Sequence Typing System for Medically Relevant Bipolaris Species

Use of Population Genetics to Assess the Ecology, Evolution, and Population Structure ofCoccidioides

Puf4 Mediates Post-transcriptional Regulation of Caspofungin Resistance inCryptococcus neoformans

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