scholarly journals Candida auris Cell Wall Mannosylation Contributes to Neutrophil Evasion through Pathways Divergent from Candida albicans and Candida glabrata

mSphere ◽  
2021 ◽  
Author(s):  
Mark V. Horton ◽  
Chad J. Johnson ◽  
Robert Zarnowski ◽  
Brody D. Andes ◽  
Taylor J. Schoen ◽  
...  
Keyword(s):  
Public Health ◽  
Fungal Pathogen ◽  
Candida Glabrata ◽  
Mortality Rates ◽  
Invasive Disease ◽  
Drug Resistant ◽  
Global Public Health ◽  
Candida Auris ◽  
Content Type ◽  
Public Health Threat

The emerging fungal pathogen Candida auris presents a global public health threat. Therapeutic options are often limited for this frequently drug-resistant pathogen, and mortality rates for invasive disease are high.

scholarly journals Impact of Candida auris Infection in a Neutropenic Murine Model

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Steven R. Torres ◽  
Amber Pichowicz ◽  
Fernando Torres-Velez ◽  
Renjie Song ◽  
Navjot Singh ◽  
...  
Keyword(s):  
Public Health ◽  
Innate Immunity ◽  
Monoclonal Antibodies ◽  
Multidrug Resistance ◽  
Murine Models ◽  
Global Public Health ◽  
Candida Auris ◽  
Innate And Adaptive Immunity ◽  
Content Type ◽  
Public Health Threat

ABSTRACT Candida auris has become a global public health threat due to its multidrug resistance and persistence. Currently, there are limited murine models to study C. auris infection. Those models use a combination of cyclophosphamide and cortisone acetate, suppressing both innate and adaptive immunity. Here, we compare C. auris infection in two neutrophil-depleted murine models in which innate immunity is targeted using the monoclonal antibodies 1A8 and RB6-8C5.

scholarly journals High-Resolution Genome-Wide Occupancy in Candida spp. Using ChEC-seq

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Faiza Tebbji ◽  
Inès Khemiri ◽  
Adnane Sellam
Keyword(s):  
Public Health ◽  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Candida Albicans ◽  
High Resolution ◽  
Transcriptional Regulator ◽  
Candida Auris ◽  
Content Type ◽  
Genome Wide ◽  
Public Health Threat

ABSTRACT To persist in their dynamic human host environments, fungal pathogens must sense and adapt by modulating their gene expression to fulfill their cellular needs. Understanding transcriptional regulation on a global scale would uncover cellular processes linked to persistence and virulence mechanisms that could be targeted for antifungal therapeutics. Infections associated with the yeast Candida albicans, a highly prevalent fungal pathogen, and the multiresistant related species Candida auris are becoming a serious public health threat. To define the set of a gene regulated by a transcriptional regulator in C. albicans, chromatin immunoprecipitation (ChIP)-based techniques, including ChIP with microarray technology (ChIP-chip) or ChIP-DNA sequencing (ChIP-seq), have been widely used. Here, we describe a new set of PCR-based micrococcal nuclease (MNase)-tagging plasmids for C. albicans and other Candida spp. to determine the genome-wide location of any transcriptional regulator of interest using chromatin endogenous cleavage (ChEC) coupled to high-throughput sequencing (ChEC-seq). The ChEC procedure does not require protein-DNA cross-linking or sonication, thus avoiding artifacts related to epitope masking or the hyper-ChIPable euchromatic phenomenon. In a proof-of-concept application of ChEC-seq, we provided a high-resolution binding map of the SWI/SNF chromatin remodeling complex, a master regulator of fungal fitness in C. albicans, in addition to the transcription factor Nsi1 that is an ortholog of the DNA-binding protein Reb1 for which genome-wide occupancy was previously established in Saccharomyces cerevisiae. The ChEC-seq procedure described here will allow a high-resolution genomic location definition which will enable a better understanding of transcriptional regulatory circuits that govern fungal fitness and drug resistance in these medically important fungi. IMPORTANCE Systemic fungal infections caused by Candida albicans and the “superbug” Candida auris are becoming a serious public health threat. The ability of these yeasts to cause disease is linked to their faculty to modulate the expression of genes that mediate their escape from the immune surveillance and their persistence in the different unfavorable niches within the host. Comprehensive knowledge on gene expression control of fungal fitness is consequently an interesting framework for the identification of essential infection processes that could be hindered by chemicals as potential therapeutics. Here, we expanded the use of ChEC-seq, a technique that was initially developed in the yeast model Saccharomyces cerevisiae to identify genes that are modulated by a transcriptional regulator, in pathogenic yeasts from the genus Candida. This robust technique will allow a better characterization of key gene expression regulators and their contribution to virulence and antifungal resistance in these pathogenic yeasts.

scholarly journals Emerging Fungal PathogenCandida aurisEvades Neutrophil Attack

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Chad J. Johnson ◽  
J. Muse Davis ◽  
Anna Huttenlocher ◽  
John F. Kernien ◽  
Jeniel E. Nett
Keyword(s):  
Invasive Candidiasis ◽  
Fungal Pathogen ◽  
Fungal Infections ◽  
Neutrophil Extracellular Traps ◽  
Invasive Disease ◽  
Human Neutrophils ◽  
Candida Auris ◽  
Zebrafish Model ◽  
Content Type ◽  
Extracellular Traps

ABSTRACTCandida aurishas recently emerged as the first fungal pathogen to cause a global public health threat. The reason this species is causing hospital-associated outbreaks of invasive candidiasis with high mortality is unknown. In this study, we examine the interaction ofC. auriswith neutrophils, leukocytes critical for control of invasive fungal infections. We show that human neutrophils do not effectively killC. auris. Compared toCandida albicans, neutrophils poorly recruited toC. aurisand failed to form neutrophil extracellular traps (NETs), which are structures of DNA, histones, and proteins with antimicrobial activity. In mixed cultures, neutrophils preferentially engaged and killedC. albicansoverC. auris. Imaging of neutrophils in a zebrafish larval model of invasive candidiasis revealed the recruitment of approximately 50% fewer neutrophils in response toC. auriscompared toC. albicans. Upon encounter withC. albicansin the zebrafish hindbrain, neutrophils produced clouds of histones, suggesting the formation of NETs. These structures were not observed inC. aurisinfection. Evasion of neutrophil attack and innate immunity offers an explanation for the virulence of this pathogen.IMPORTANCEThe emerging fungal pathogenCandida aurishas produced numerous outbreaks of invasive disease in hospitals worldwide. Why this species causes deadly disease is unknown. Our findings reveal a failure of neutrophils to killC. auriscompared to the most commonly encounteredCandidaspecies,C. albicans. While neutrophils produce neutrophil extracellular traps (NETs) upon encounter withC. albicans, these antimicrobial structures are not formed in response toC. auris. Using human neutrophils and a zebrafish model of invasive candidiasis, we show thatC. aurispoorly recruits neutrophils and evades immune attack. Identification of this impaired innate immune response toC. aurissheds light on the dismal outcomes for patients with invasive disease.

scholarly journals Comparative Pathogenicity of United Kingdom Isolates of the Emerging Pathogen Candida auris and Other Key Pathogenic Candida Species

mSphere ◽  
2016 ◽  
Vol 1 (4) ◽  
Author(s):  
Andrew M. Borman ◽  
Adrien Szekely ◽  
Elizabeth M. Johnson
Keyword(s):  
Invasive Candidiasis ◽  
Fungal Pathogen ◽  
Galleria Mellonella ◽  
Systemic Infection ◽  
Mortality Rates ◽  
Infection Model ◽  
Candida Auris ◽  
Deep Tissue ◽  
Content Type

ABSTRACT The incidence of invasive candidiasis, which includes candidemia and deep tissue infections, continues to rise and is associated with considerable mortality rates. Candida albicans remains the most common cause of invasive candidiasis, although the prevalence of non-albicans species has increased over recent years. Since its first description in 2009, Candida auris has emerged as a serious nosocomial health risk, with widespread outbreaks in numerous hospitals worldwide. However, despite receiving considerable attention, little is known concerning the pathogenicity of this emerging fungal pathogen. Here, using the Galleria mellonella insect systemic infection model, we show strain-specific differences in the virulence of C. auris, with the most virulent isolates exhibiting pathogenicity comparable to that of C. albicans, which is currently accepted as the most pathogenic member of the genus. Candida auris, first described in 2009, has since emerged as an important, multidrug-resistant, nosocomial agent of candidemia, with large outbreaks reported worldwide and high mortality rates associated with therapeutic failure. The current study employed C. auris isolates from a variety of centers in the United Kingdom to evaluate the pathogenicity of this emerging pathogen compared to that of other common pathogenic yeast species in the invertebrate Galleria mellonella infection model. We showed that C. auris isolates differ in their growth characteristics in vitro, with a proportion of isolates failing to release daughter cells after budding, resulting in the formation of large aggregates of cells that cannot be physically disrupted. Our results also demonstrate strain-specific differences in the behavior of C. auris in G. mellonella, with the aggregate-forming isolates exhibiting significantly less pathogenicity than their nonaggregating counterparts. Importantly, the nonaggregating isolates exhibited pathogenicity comparable to that of C. albicans, which is currently accepted as the most pathogenic member of the genus, despite the fact that C. auris isolates do not produce hyphae and produce only rudimentary pseudohyphae either in vitro or in G. mellonella. IMPORTANCE The incidence of invasive candidiasis, which includes candidemia and deep tissue infections, continues to rise and is associated with considerable mortality rates. Candida albicans remains the most common cause of invasive candidiasis, although the prevalence of non-albicans species has increased over recent years. Since its first description in 2009, Candida auris has emerged as a serious nosocomial health risk, with widespread outbreaks in numerous hospitals worldwide. However, despite receiving considerable attention, little is known concerning the pathogenicity of this emerging fungal pathogen. Here, using the Galleria mellonella insect systemic infection model, we show strain-specific differences in the virulence of C. auris, with the most virulent isolates exhibiting pathogenicity comparable to that of C. albicans, which is currently accepted as the most pathogenic member of the genus.

scholarly journals The Emergence of Extensively Drug-Resistant Tuberculosis (TB): TB/HIV Coinfection, Multidrug-Resistant TB and the Resulting Public Health Threat from Extensively Drug-Resistant TB, Globally and in Canada

2007 ◽  
Vol 18 (5) ◽  
pp. 289-291 ◽  
Author(s):  
Paul E Alexander ◽  
Prithwish De
Keyword(s):  
Public Health ◽  
Multidrug Resistant ◽  
Current Status ◽  
Drug Resistant ◽  
Global Public Health ◽  
Access To Treatment ◽  
Health Threat ◽  
Extensively Drug Resistant ◽  
Hiv Coinfection ◽  
Public Health Threat

Resistance to anti-tuberculosis (TB) drugs continues to present a major challenge to global public health. Resistance usually develops due to inadequate TB management, including improper use of medications, improper treatment regimens and failure to complete the treatment course. This may be due to an erratic supply or a lack of access to treatment, as well as to patient noncompliance. However, the emergence and transmission of drug-resistant TB, including the recently detected extensively drug resistant TB (XDR-TB), is driven, in part, by the synergistic relationship between TB and HIV (TB/HIV coinfection). There is evidence that persons infected with HIV are more likely to experience XDR-TB. XDR-TB is virtually untreatable with available TB medications. XDR-TB presents a grave global public health threat, particularly in high HIV prevalence settings. The present commentary discusses the current status of XDR-TB and draws attention to the urgency in addressing this problem, for both the global and Canadian public health networks. XDR-TB and the apparent XDR-TB and HIV association warrants further study.

scholarly journals Assessment of the In Vitro and In Vivo Antifungal Activity of NSC319726 against Candida auris

2021 ◽  
Author(s):  
Jizhou Li ◽  
Alix T. Coste ◽  
Daniel Bachmann ◽  
Dominique Sanglard ◽  
Frederic Lamoth
Keyword(s):  
Public Health ◽  
Antifungal Activity ◽  
Invasive Candidiasis ◽  
Multidrug Resistant ◽  
Candida Auris ◽  
Content Type ◽  
Health Threat ◽  
Public Health Threat

Candida auris is emerging as a major public health threat because of its ability to cause nosocomial outbreaks of severe invasive candidiasis. Management of C. auris infection is difficult because of its frequent multidrug-resistant profile for currently licensed antifungals.

scholarly journals Experimental Mouse Models of Disseminated Candida auris Infection

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Hong Xin ◽  
Farhan Mohiuddin ◽  
Jensen Tran ◽  
Abby Adams ◽  
Karen Eberle
Keyword(s):  
Mouse Model ◽  
Fungal Pathogen ◽  
The United States ◽  
Multidrug Resistant ◽  
Host Responses ◽  
High Dose ◽  
Invasive Infection ◽  
Global Public Health ◽  
Candida Auris ◽  
Content Type

ABSTRACT Disseminated candidiasis is a life-threatening disease and remains the most common bloodstream infection in hospitalized patients in the United States. Despite the availability of modern antifungal therapy, crude mortality in the last decade has remained unacceptably high. In particular, Candida auris is a multidrug-resistant, health care-associated fungal pathogen and has recently emerged as the first fungal pathogen to cause a global public health threat. A reliable animal model for disseminated C. auris candidiasis is therefore needed to study the unique aspects of this little-known host-pathogen interaction. In this study, we established an inbred A/J intravenous model as an appropriate model for human disseminated C. auris infection. We found that C5 deficiency in A/J mice results in a complex phenotype characterized by rapid fungal proliferation in target organs and the development of a unique and rapidly fatal response. In contrast, C57BL/6J mice and mice deficient in neutrophil elastase (NE−/−) survived high-dose C. auris intravenous challenge, even with cyclophosphamide (CY)-induced immunosuppression. Our study is the first to provide insight into the role of C5 in the host responses to C. auris invasive infection and establishes an inbred A/J mouse model of systemic C. auris infection without CY-induced immunosuppression. IMPORTANCE In the last decade, Candida auris has emerged globally as a multidrug‐resistant fungal pathogen. Although C. auris was initially isolated from the external ear canal, it can cause outbreaks of invasive infections with very high mortality and comorbidities. Recent reports highlight the ongoing challenges due to organism misidentification, high rates of multifungal drug resistance, and unacceptably high patient mortality. The assessment of C. auris virulence in a specific genetic deficiency mouse model of invasive C. auris infection in this study contributes to the little knowledge of host defense to C. auris infection, which holds promise as a model for investigating the pathogenesis of C. auris invasive infection, exploring the immune responses elicited by the fungus, evaluating the possible induction of immunity to the infection, and targeting candidates for an antifungal vaccine.

scholarly journals Genetic diversity and drug susceptibility patterns of the Mycobacterium tuberculosis complex in Yunnan, China

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Ruolan Bai ◽  
Shuijing Chi ◽  
Xiaofei Li ◽  
Xiting Dai ◽  
Zhenhua Ji ◽  
...  
Keyword(s):  
Public Health ◽  
Genetic Diversity ◽  
Mycobacterium Tuberculosis ◽  
Public Health Problem ◽  
Drug Susceptibility ◽  
Drug Resistant ◽  
Global Public Health ◽  
High Genetic Diversity ◽  
Dominant Feature ◽  
Mdr Tb

AbstractTuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) which has been threatening global public health for many years. High genetic diversity is dominant feature of Mtb. Increasing cases of multidrug-resistant (MDR) tuberculosis (MDR-TB) is a serious public health problem to TB control in China. Spontaneous mutations in the Mtb genome can alter proteins which are the target of drugs, making the bacteria drug resistant. The purpose of the present study was to analyze the genotype of Mtb isolates from some areas in Yunnan, China and explore the association between genotypes and MDR-TB. Using spoligotyping, we identified Beijing genotypes, six non-Beijing genotypes and a number of orphan genotypes from 270 Mtb isolates from patients in Yunnan Province during 2014–2016. Of 270 Mtb isolates, 102 clinical Mtb strains were identified as drug-resistant (DR) by drug susceptibility testing (DST), among them, 52 MDR strains. Beijing genotypes occupied the highest MDR proportion (78.85%) followed by the orphan genotypes (15.38%). The characteristics of MDR strains showed high genetic diversity. The results will help to efficiently improve diagnosis and treatment and provide valuable information for Mtb molecular epidemiology.

scholarly journals Dynamics of blaKPC-2 Dissemination from Non-CG258 Klebsiella pneumoniae to Other Enterobacterales via IncN Plasmids in an Area of High Endemicity

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Ana M. Rada ◽  
Elsa De La Cadena ◽  
Carlos Agudelo ◽  
Cesar Capataz ◽  
Nataly Orozco ◽  
...  
Keyword(s):  
Public Health ◽  
Klebsiella Pneumoniae ◽  
Neonatal Intensive Care ◽  
Carbapenem Resistance ◽  
Health Interventions ◽  
Global Public Health ◽  
Public Health Interventions ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Long Read

ABSTRACT Carbapenem-resistant Enterobacterales (CRE) pose a significant threat to global public health. The most important mechanism for carbapenem resistance is the production of carbapenemases. Klebsiella pneumoniae carbapenemase (KPC) represents one of the main carbapenemases worldwide. Complex mechanisms of blaKPC dissemination have been reported in Colombia, a country with a high endemicity of carbapenem resistance. Here, we characterized the dynamics of dissemination of blaKPC gene among CRE infecting and colonizing patients in three hospitals localized in a highly endemic area of Colombia (2013 and 2015). We identified the genomic characteristics of KPC-producing Enterobacterales recovered from patients infected/colonized and reconstructed the dynamics of dissemination of blaKPC-2 using both short and long read sequencing. We found that spread of blaKPC-2 among Enterobacterales in the participating hospitals was due to intra- and interspecies horizontal gene transfer (HGT) mediated by promiscuous plasmids associated with transposable elements that was originated from a multispecies outbreak of KPC-producing Enterobacterales in a neonatal intensive care unit. The plasmids were detected in isolates recovered in other units within the same hospital and nearby hospitals. The gene “epidemic” was driven by IncN-pST15-type plasmids carrying a novel Tn4401b structure and non-Tn4401 elements (NTEKPC) in Klebsiella spp., Escherichia coli, Enterobacter spp., and Citrobacter spp. Of note, mcr-9 was found to coexist with blaKPC-2 in species of the Enterobacter cloacae complex. Our findings suggest that the main mechanism for dissemination of blaKPC-2 is HGT mediated by highly transferable plasmids among species of Enterobacterales in infected/colonized patients, presenting a major challenge for public health interventions in developing countries such as Colombia.

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