Advances in the understanding of the Cryptococcus neoformans and C. gattii species complexes and cryptococcosis

2017 ◽  
Vol 38 (3) ◽  
pp. 106
Author(s):  
Carolina Firacative ◽  
Luciana Trilles ◽  
Wieland Meyer
Keyword(s):  
Cryptococcus Neoformans ◽  
Sibling Species ◽  
Treatment Options ◽  
Antifungal Susceptibility ◽  
Disease Outbreaks ◽  
Accurate Identification ◽  
Fungal Virulence ◽  
Species Complexes ◽  
Interdisciplinary Projects ◽  
Etiological Agents

The rising incidence of cryptococcosis, a potentially fatal fungal infection affecting both immunocompromised and immunocompetent humans and animals, and the emergence of disease outbreaks, has increased the need for more in-depth studies and constant vigilance of its two etiological agents, the cosmopolitan and well known Cryptococcus neoformans and its sibling species C. gattii. As a result, a global scientific network has established formal links between institutions to gain better insights into Cryptococcus and cryptococcosis, enabling collaborations amongst researchers with different backgrounds, perspectives and skills. Interdisciplinary projects include: (1) the study of the ecology and geographical distribution of the agents of cryptococcosis; (2) the application of new alternative methodologies for the rapid and accurate identification of the two sibling species and major molecular types/possible cryptic species (VNI-VNIV and VGI-VGIV); (3) the use of different animal models of infection to assess cryptococcal pathogenesis and virulence factors; and (4) population genetics studies directed towards the discovery of virulence/tissue tropism associated genetic signatures. These studies enrich the knowledge and understanding of the epidemiology of this mycosis and help to better comprehend fungal virulence, genetics, pathogenesis, antifungal susceptibility, as well as investigating the regional and global spread, to improve treatment options of the disease caused by these important emerging pathogenic yeasts.

scholarly journals Cryptococcus neoformans and Cryptococcus gattii Species Complexes in Latin America: A Map of Molecular Types, Genotypic Diversity, and Antifungal Susceptibility as Reported by the Latin American Cryptococcal Study Group

2021 ◽  
Vol 7 (4) ◽  
pp. 282
Author(s):  
Carolina Firacative ◽  
Wieland Meyer ◽  
Elizabeth Castañeda
Keyword(s):  
Latin America ◽  
Cryptococcus Neoformans ◽  
Latin American ◽  
Antifungal Susceptibility ◽  
Genotypic Diversity ◽  
Cryptococcus Gattii ◽  
Study Group ◽  
Molecular Type ◽  
Infected People ◽  
Species Complexes

Cryptococcosis, a potentially fatal mycosis, is caused by members of the Cryptococcus neoformans and Cryptococcus gattii species complexes. In Latin America, cryptococcal meningitis is still an important health threat with a significant clinical burden. Analysis of publicly available molecular data from 5686 clinical, environmental, and veterinary cryptococcal isolates from member countries of the Latin American Cryptococcal Study Group showed that, as worldwide, C. neoformans molecular type VNI is the most common cause of cryptococcosis (76.01%) in HIV-infected people, followed by C. gattii molecular type VGII (12.37%), affecting mostly otherwise healthy hosts. These two molecular types also predominate in the environment (68.60% for VNI and 20.70% for VGII). Among the scarce number of veterinary cases, VGII is the predominant molecular type (73.68%). Multilocus sequence typing analysis showed that, in Latin America, the C. neoformans population is less diverse than the C. gattii population (D of 0.7104 vs. 0.9755). Analysis of antifungal susceptibility data showed the presence of non-wild-type VNI, VGI, VGII, and VGIII isolates in the region. Overall, the data presented herein summarize the progress that has been made towards the molecular epidemiology of cryptococcal isolates in Latin America, contributing to the characterization of the genetic diversity and antifungal susceptibility of these globally spreading pathogenic yeasts.

scholarly journals Lipid Flippase Subunit Cdc50 Mediates Drug Resistance and Virulence inCryptococcus neoformans

mBio ◽  
2016 ◽  
Vol 7 (3) ◽  
Author(s):  
Wei Huang ◽  
Guojian Liao ◽  
Gregory M. Baker ◽  
Yina Wang ◽  
Richard Lau ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Treatment Options ◽  
Membrane Lipid ◽  
Fungal Resistance ◽  
Fungal Virulence ◽  
Innate Resistance ◽  
Fungal Meningitis ◽  
Lipid Flippase

ABSTRACTCryptococcus neoformansis a human fungal pathogen and a major cause of fungal meningitis in immunocompromised individuals. Treatment options for cryptococcosis are limited. Of the two major antifungal drug classes, azoles are active againstC. neoformansbut exert a fungistatic effect, necessitating long treatment regimens and leaving open an avenue for emergence of azole resistance. Drugs of the echinocandin class, which target the glucan synthase and are fungicidal against a number of other fungal pathogens, such asCandidaspecies, are ineffective againstC. neoformans. Despite the sensitivity of the target enzyme to the drug, the reasons for the innate resistance ofC. neoformansto echinocandins remain unknown. To understand the mechanism of echinocandin resistance inC. neoformans, we screened gene disruption and gene deletion libraries for mutants sensitive to the echinocandin-class drug caspofungin and identified a mutation ofCDC50, which encodes the β-subunit of membrane lipid flippase. We found that the Cdc50 protein localized to membranes and that its absence led to plasma membrane defects and enhanced caspofungin penetration into the cell, potentially explaining the increased caspofungin sensitivity. Loss ofCDC50also led to hypersensitivity to the azole-class drug fluconazole. Interestingly, in addition to functioning in drug resistance,CDC50was also essential for fungal resistance to macrophage killing and for virulence in a murine model of cryptococcosis. Furthermore, the surface ofcdc50Δcells contained increased levels of phosphatidylserine, which has been proposed to act as a macrophage recognition signal. Together, these results reveal a previously unappreciated role of membrane lipid flippase inC. neoformansdrug resistance and virulence.IMPORTANCECryptococcus neoformansis a fungal pathogen that is the most common cause of fungal meningitis, causing over 620,000 deaths annually. The treatment options for cryptococcosis are very limited. The most commonly used drugs are either fungistatic (azoles) or highly toxic (amphotericin B). Echinocandins are the newest fungicidal drug class that works well in treating candidiasis and aspergillosis, yet they are ineffective in treating cryptococcosis. In this study, we showed that the regulatory subunit of the lipid translocase (flippase), a protein that regulates the asymmetrical orientation of membrane lipids, is required forC. neoformansresistance to caspofungin, as well as for virulence during infection. This discovery identifies lipid flippase as a potentialC. neoformansdrug target, which plays an important role in the innate resistance ofC. neoformansto echinocandins and in fungal virulence.

scholarly journals Prevalence, Genetic Structure, and Antifungal Susceptibility of the Cryptococcus neoformans/C. gattii Species Complex Strains Collected from the Arboreal Niche in Poland

Pathogens ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 8
Author(s):  
Magdalena Florek ◽  
Agnieszka Korzeniowska-Kowal ◽  
Anna Wzorek ◽  
Katarzyna Włodarczyk ◽  
Maja Marynowska ◽  
...  
Keyword(s):  
Genetic Structure ◽  
Cryptococcus Neoformans ◽  
Species Complex ◽  
Central And Eastern Europe ◽  
Antifungal Susceptibility ◽  
Environmental Study ◽  
Wild Type ◽  
Molecular Type ◽  
Pathogen Population ◽  
Etiological Agents

Fungi belonging to the Cryptococcus neoformans/C. gattii species complex (CNGSC) are etiological agents of serious and not infrequently fatal infections in both humans and animals. Trees are the main ecological niche and source of potential exposition concerning these pathogens. With regard to epidemiology of cryptococcosis, various surveys were performed worldwide, enabling the establishment of a map of distribution and genetic structure of the arboreal population of the CNGSC. However, there are regions, among them Central and Eastern Europe, in which the data are lacking. The present study shows the results of such an environmental study performed in Wrocław, Poland. The CNGSC strains were detected in 2.2% of the tested trees belonging to four genera. The obtained pathogen population consisted exclusively of C. neoformans, represented by both the major molecular type VNI and VNIV. Within the tested group of isolates, resistance to commonly used antimycotics was not found, except for 5-fluorocytosine, in which about 5% of the strains were classified as a non-wild type.

scholarly journals Recent Advances in Cryptococcus and Cryptococcosis

2021 ◽  
Vol 10 (1) ◽  
pp. 13
Author(s):  
Carolina Firacative ◽  
Luciana Trilles ◽  
Wieland Meyer
Keyword(s):  
Risk Factors ◽  
Fungal Infection ◽  
Cryptococcus Neoformans ◽  
Cryptococcus Gattii ◽  
Recent Advances ◽  
Species Complexes ◽  
Life Threatening ◽  
Etiological Agents

The members of the Cryptococcus neoformans and Cryptococcus gattii species complexes are the main etiological agents of cryptococcosis, a life-threatening fungal infection affecting mostly immunocompromised people, but also immunocompetent hosts or those with unrecognized risk factors [...]

Molecular types of Cryptococcus neoformans and Cryptococcus gattii in Western Australia and correlation with antifungal susceptibility

2019 ◽  
Vol 57 (8) ◽  
pp. 1004-1010 ◽  
Author(s):  
Gar-hing Andrew Lee ◽  
Ian Arthur ◽  
Adam Merritt ◽  
Michael Leung
Keyword(s):  
Cryptococcus Neoformans ◽  
Antifungal Agents ◽  
Geometric Mean ◽  
Antifungal Susceptibility ◽  
Cryptococcus Gattii ◽  
Molecular Type ◽  
Australian Population ◽  
Worldwide Distribution ◽  
Species Complexes ◽  
Western Australian

AbstractCryptococcus neoformans and Cryptococcus gattii species complexes have a worldwide distribution; however, there is geographical variation in the prevalence of different molecular types. Additionally, antifungal susceptibility differences between molecular types have been demonstrated. This study investigates the distribution of cryptococcal molecular types among human clinical isolates over a 10-year period from a Western Australian population. Molecular type was determined based on polymorphisms in the phospholipase gene locus identified through amplification and sequencing. Minimum inhibitory concentrations (MICs) were identified for fluconazole, 5-fluorocytosine, posaconazole, itraconazole, voriconazole, and amphotericin B. Most isolates were C. neoformans complex (42) of which over half were molecular type VNI (22) followed by VNII (20). Among the remaining C. gattii complex (13) the majority were VGI (11) with VGII (2) uncommonly found. All isolates demonstrated low MICs to antifungal agents including fluconazole. Geometric mean MIC values against 5-fluorocytosine for VNI (1.741 mg/l) were significantly higher than those for VGI (0.47 mg/l, P = .002). Similarly fluconazole geometric mean MICs against fluconazole for VNI (2.3 mg/l) were significantly higher than VNII (0.87 mg/l, P = .036). These data reveal the presence of four molecular types (VNI, VNII, VGI and VGII) within clinical Western Australian cryptococcal isolates and, while elevated antifungal MICs were not encountered, significant molecular type dependent differences in susceptibility were found.

scholarly journals 549. Clinical Characteristics and Outcomes of Patients with COVID-19 treated with Convalescent Plasma in Miami, Florida

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S340-S341
Author(s):  
Shweta Anjan ◽  
Dimitra Skiada ◽  
Miriam Andrea Duque Cuartas ◽  
Douglas Salguero ◽  
David P Serota ◽  
...  
Keyword(s):  
Treatment Options ◽  
Disease Outbreaks ◽  
Nasopharyngeal Swab ◽  
Rt Pcr ◽  
Health Crisis ◽  
Infectious Disease Outbreaks ◽  
Reactive Protein ◽  
High Acuity ◽  
Us Fda ◽  
Oxygen Requirements

Abstract Background The Coronavirus disease of 2019 (COVID-19) global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in unprecedented mortality, impacted society, and strained healthcare systems, yet sufficient data regarding treatment options are lacking. Convalescent plasma, used since 1895 for infectious disease outbreaks, offers promise as a treatment option for COVID-19. Methods This is a retrospective study of patients diagnosed by a nasopharyngeal swab SARS-CoV-2 reverse transcriptase–polymerase chain reaction (RT-PCR), who received convalescent plasma between April to June 2020 at two large hospitals in Miami, Florida, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma (CCP). Results A total of 23 patients received CCP, 13 (57%) had severe COVID-19 disease, while 8 (35%) had critical or critical with multiorgan dysfunction. Median time of follow up was 26 (range, 7–79) days. Overall, 11 (48%) survived to discharge, 6 (26%) died, while 6 (26%) are currently hospitalized. All deaths reported were due to septic shock from secondary infections. 15 (65%) showed improvement in oxygen requirements 7 days post CCP transfusion. Measured inflammatory markers, c-reactive protein, lactate dehydrogenase, ferritin and d-dimer improved 7 days post transfusion in 13 (57%) patients. No adverse events due to the transfusion were reported. 10 (43.4%) patients had a negative SARS-CoV-2 RT-PCR at a median of 14.5 (range, 4–31) days after receiving convalescent plasma. Conclusion Administration of convalescent plasma was found to be safe, with favorable outcomes in this small cohort of relatively high acuity patients. Larger studies including control arms are needed to establish the efficacy of convalescent plasma on clinical and virologic outcomes for patients with COVID-19. Table Disclosures All Authors: No reported disclosures

scholarly journals Trends in Antifungal Drug Susceptibility of Cryptococcus neoformans Isolates Obtained through Population-Based Surveillance in South Africa in 2002-2003 and 2007-2008

2011 ◽  
Vol 55 (6) ◽  
pp. 2606-2611 ◽  
Author(s):  
Nelesh P. Govender ◽  
Jaymati Patel ◽  
Marelize van Wyk ◽  
Tom M. Chiller ◽  
Shawn R. Lockhart ◽  
...  
Keyword(s):  
South Africa ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Drug Susceptibility ◽  
Population Based ◽  
Content Type ◽  
Microdilution Method ◽  
Broth Microdilution Method

ABSTRACTCryptococcus neoformansis the most common cause of meningitis among adult South Africans with HIV infection/AIDS. Widespread use of fluconazole for treatment of cryptococcal meningitis and other HIV-associated opportunistic fungal infections in South Africa may lead to the emergence of isolates with reduced fluconazole susceptibility. MIC testing using a reference broth microdilution method was used to determine if isolates with reduced susceptibility to fluconazole or amphotericin B had emerged among cases of incident disease. Incident isolates were tested from two surveillance periods (2002-2003 and 2007-2008) when population-based surveillance was conducted in Gauteng Province, South Africa. These isolates were also tested for susceptibility to flucytosine, itraconazole, voriconazole, and posaconazole. Serially collected isolate pairs from cases at several large South African hospitals were also tested for susceptibility to fluconazole. Of the 487 incident isolates tested, only 3 (0.6%) demonstrated a fluconazole MIC of ≥16 μg/ml; all of these isolates were from 2002-2003. All incident isolates were inhibited by very low concentrations of amphotericin B and exhibited very low MICs to voriconazole and posaconazole. Of 67 cases with serially collected isolate pairs, only 1 case was detected where the isolate collected more than 30 days later had a fluconazole MIC value significantly higher than the MIC of the corresponding incident isolate. Although routine antifungal susceptibility testing of incident isolates is not currently recommended in clinical settings, it is still clearly important for public health to periodically monitor for the emergence of resistance.

FUSARIUM-ID v.3.0: An updated, downloadable resource for Fusarium species identification

Plant Disease ◽  
2021 ◽  
Author(s):  
Terry Torres-Cruz ◽  
Briana Whitaker ◽  
Robert Proctor ◽  
Kirk Broders ◽  
Imane Laraba ◽  
...  
Keyword(s):  
Sequence Data ◽  
Safety Concern ◽  
Fusarium Species ◽  
Elongation Factor ◽  
Sequence Database ◽  
Accurate Identification ◽  
Dna Sequence Data ◽  
Species Complexes ◽  
Marker Loci ◽  
Feed Safety

Species within Fusarium are of global agricultural, medical, and food/feed safety concern and have been extensively characterized. However, accurate identification of species is challenging and usually requires DNA sequence data. FUSARIUM-ID (http://isolate.fusariumdb.org/) is a publicly available database designed to support the identification of Fusarium species using sequences of multiple phylogenetically informative loci, especially the highly informative ~680 bp 5' portion of the translation elongation factor 1-alpha (TEF1) gene that has been adopted as the primary barcoding locus in the genus. However, FUSARIUM-ID v.1.0 and 2.0 had several limitations, including inconsistent metadata annotation for the archived sequences and poor representation of some species complexes and marker loci. Here, we present FUSARIUM-ID v.3.0, which provides the following improvements: (i) additional and updated annotation of metadata for isolates associated with each sequence, (ii) expanded taxon representation in the TEF1 sequence database, (iii) availability of the sequence database as a downloadable file to enable local BLAST queries, and (iv) a tutorial file for users to perform local BLAST searches using either freely-available software, such as SequenceServer, BLAST+ executable in the command line, and Galaxy, or the proprietary Geneious software. FUSARIUM-ID will be updated on a regular basis by archiving sequences of TEF1 and other loci from newly identified species and greater in-depth sampling of currently recognized species.

scholarly journals A Mechanosensitive Channel Governs Lipid Flippase-Mediated Echinocandin Resistance in Cryptococcus neoformans

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Chengjun Cao ◽  
Yina Wang ◽  
Seema Husain ◽  
Patricia Soteropoulos ◽  
Chaoyang Xue
Keyword(s):  
Cryptococcus Neoformans ◽  
Calcium Homeostasis ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Regulatory Subunit ◽  
Mechanosensitive Channel ◽  
Content Type ◽  
Echinocandin Resistance ◽  
Lipid Flippase ◽  
Calcineurin Pathway

ABSTRACT Echinocandins show fungicidal activity against common invasive mycoses but are ineffective against cryptococcosis. The underlying mechanism for echinocandin resistance in Cryptococcus neoformans remains poorly understood but has been shown to involve Cdc50, the regulatory subunit of lipid flippase. In a forward genetic screen for cdc50Δ suppressor mutations that are caspofungin resistant, we identified Crm1 (caspofungin resistant mutation 1), a homolog of mechanosensitive channel proteins, and showed that crm1Δ restored caspofungin resistance in cdc50Δ cells. Caspofungin-treated cdc50Δ cells exhibited abnormally high intracellular calcium levels ([Ca2+]c) and heightened activation of the calcineurin pathway. Deletion of CRM1 in the cdc50Δ background normalized the abnormally high [Ca2+]c. Cdc50 interacts with Crm1 to maintain cellular calcium homeostasis. Analysis of chitin/chitosan content showed that deleting CRM1 reversed the decreased chitosan production of cdc50Δ cells. Together, these results demonstrate that Cdc50 and Crm1 regulation of the calcineurin pathway and cytoplasmic calcium homeostasis may underlie caspofungin resistance in C. neoformans. IMPORTANCE Cryptococcus neoformans is the leading cause of fungal meningitis, accounting for ∼15% of HIV/AIDS-related deaths, but treatment options for cryptococcosis are limited. Echinocandins are the newest fungicidal drug class introduced but are ineffective in treating cryptococcosis. Our previous study identified the lipid flippase subunit Cdc50 as a contributor to echinocandin resistance in C. neoformans. Here, we further elucidated the mechanism of Cdc50-mediated caspofungin drug resistance. We discovered that Cdc50 interacts with the mechanosensitive calcium channel protein Crm1 to regulate calcium homeostasis and caspofungin resistance via calcium/calcineurin signaling. These results provide novel insights into echinocandin resistance in this pathogen, which may lead to new treatment options, as well as inform echinocandin resistance mechanisms in other fungal organisms and, hence, advance our understanding of modes of antifungal drug susceptibility and resistance.

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