The role of<i>Candida albicans</i>AP-1 protein against host derived ROS in in vivo models of infection

Jain, Charu; Pastor, Kelly; Gonzalez, Arely Y; Lorenz, Michael; Rao, Reeta P.

doi:10.4161/viru.22700

Cited by 41 publications

(57 citation statements)

References 79 publications

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“…We used a reverse genetic approach to identify genes required for virulence during infection of a live host by screening a collection of 724 C. albicans mutants (10% of the genome) (Table S2) using C. elegans as a model host (Jain et al 2013). C. elegans is a useful model to study infectious disease.…”

Section: Resultsmentioning

confidence: 99%

“…Live nematodes were infected with C. albicans to identify mutants that exhibited altered phenotype in the worms. The assays have previously been described (Jain et al 2013). Briefly, 30 healthy C. elegans were exposed to C. albicans, which was mixed into their diet (Jain et al 2009).…”

Section: Reverse Genetic Screen and In Vivo Virulence Assaysmentioning

confidence: 99%

“…Briefly, 30 healthy C. elegans were exposed to C. albicans, which was mixed into their diet (Jain et al 2009). The percentage of worms showing signs of infection (Jain et al 2013) were scored manually 4 days post infection. To generate survival curves, 20 young synchronized C. elegans N2 were exposed to the infection diet.…”

Section: Reverse Genetic Screen and In Vivo Virulence Assaysmentioning

confidence: 99%

“…We employed experimentally tractable in vivo and ex vivo models to elucidate the role of these ZCF TFs in the innate immune system (Jain et al 2009(Jain et al , 2013. Among the 35 ZCFs, these mutants exhibit similar redox sensitivity profiles in phagocytes ex vivo, and nematodes in vivo.…”

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confidence: 99%

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Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

et al. 2017

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Almost all humans are colonized with Candida albicans. However, in immunocompromised individuals, this benign commensal organism becomes a serious, life-threatening pathogen. Here, we describe and analyze the regulatory networks that modulate innate responses in the host niches. We identified Zcf15 and Zcf29, two Zinc Cluster transcription Factors (ZCF) that are required for C. albicans virulence. Previous sequence analysis of clinical C. albicans isolates from immunocompromised patients indicates that both ZCF genes diverged during clonal evolution. Using in vivo animal models, ex vivo cell culture methods, and in vitro sensitivity assays, we demonstrate that knockout mutants of both ZCF15 and ZCF29 are hypersensitive to reactive oxygen species (ROS), suggesting they help neutralize the host-derived ROS produced by phagocytes, as well as establish a sustained infection in vivo. Transcriptomic analysis of mutants under resting conditions where cells were not experiencing oxidative stress revealed a large network that control macro and micronutrient homeostasis, which likely contributes to overall pathogen fitness in host niches. Under oxidative stress, both transcription factors regulate a separate set of genes involved in detoxification of ROS and down-regulating ribosome biogenesis. ChIP-seq analysis, which reveals vastly different binding partners for each transcription factor (TF) before and after oxidative stress, further confirms these results. Furthermore, the absence of a dominant binding motif likely facilitates their mobility, and supports the notion that they represent a recent expansion of the ZCF family in the pathogenic Candida species. Our analyses provide a framework for understanding new aspects of the interface between C. albicans and host defense response, and extends our understanding of how complex cell behaviors are linked to the evolution of TFs.

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Section: Resultsmentioning

confidence: 99%

Section: Reverse Genetic Screen and In Vivo Virulence Assaysmentioning

confidence: 99%

Section: Reverse Genetic Screen and In Vivo Virulence Assaysmentioning

confidence: 99%

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confidence: 99%

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Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

et al. 2017

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“…In addition to our in vitro assays, we tested whether filastatin affects fungal infections in vivo. We used the previously described deformed anal region (Dar) tail-swelling phenotype (16,32) as a biomarker to monitor fungal infections in nematode hosts. A small quantity of C. albicans was introduced with the nematode's standard diet of Escherichia coli OP50 cells, and E. coli growth was attenuated with the antibiotic streptomycin to avoid interactions with C. albicans (33).…”

Section: Filastatin Exhibits Antifungal Activity In a Nematode Model Ofmentioning

confidence: 99%

Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis

Fazly¹,

Jain

Dehner³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Infection by pathogenic fungi, such as Candida albicans, begins with adhesion to host cells or implanted medical devices followed by biofilm formation. By high-throughput phenotypic screening of small molecules, we identified compounds that inhibit adhesion of C. albicans to polystyrene. Our lead candidate compound also inhibits binding of C. albicans to cultured human epithelial cells, the yeast-to-hyphal morphological transition, induction of the hyphal-specific HWP1 promoter, biofilm formation on silicone elastomers, and pathogenesis in a nematode infection model as well as alters fungal morphology in a mouse mucosal infection assay. We term this compound filastatin based on its strong inhibition of filamentation, and we use chemical genetic experiments to show that it acts downstream of multiple signaling pathways. These studies show that high-throughput functional assays targeting fungal adhesion can provide chemical probes for study of multiple aspects of fungal pathogenesis.hyphal morphogenesis | small molecule screening | fungal pathogens

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Virulence phenotypes result from interactions between pathogen ploidy and genetic background

Feistel

Elmostafa

Hickman

2020

Ecology and Evolution

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Studying fungal virulence is often challenging and frequently depends on many contexts, including host immune status and pathogen genetic background. However, the role of ploidy has often been overlooked when studying virulence in eukaryotic pathogens. Since fungal pathogens, including the human opportunistic pathogen Candida albicans, can display extensive ploidy variation, assessing how ploidy impacts virulence has important clinical relevance. As an opportunistic pathogen, C. albicans causes nonlethal, superficial infections in healthy individuals, but life‐threatening bloodstream infections in individuals with compromised immune function. Here, we determined how both ploidy and genetic background of C. albicans impacts virulence phenotypes in healthy and immunocompromised nematode hosts by characterizing virulence phenotypes in four near‐isogenic diploid and tetraploid pairs of strains, which included both laboratory and clinical genetic backgrounds. We found that C. albicans infections decreased host survival and negatively impacted host reproduction, and we leveraged these two measures to survey both lethal and nonlethal virulence phenotypes across the multiple C. albicans strains. In this study, we found that regardless of pathogen ploidy or genetic background, immunocompromised hosts were susceptible to fungal infection compared to healthy hosts. Furthermore, for each host context, we found a significant interaction between C. albicans genetic background and ploidy on virulence phenotypes, but no global differences between diploid and tetraploid pathogens were observed.

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The role ofCandida albicansAP-1 protein against host derived ROS in in vivo models of infection

Cited by 41 publications

References 79 publications

Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

Zinc Cluster Transcription Factors Alter Virulence in Candida albicans

Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis

Virulence phenotypes result from interactions between pathogen ploidy and genetic background

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