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Disarming Fungal Pathogens: Bacillus safensis Inhibits Virulence Factor Production and Biofilm Formation by Cryptococcus neoformans and Candida albicans.

ABSTRACT: Bacteria interact with each other in nature and often compete for limited nutrient and space resources. However, it is largely unknown whether and how bacteria also interact with human fungal pathogens naturally found in the environment. Here, we identified a soil bacterium, Bacillus safensis, which potently blocked several key Cryptococcus neoformans virulence factors, including formation of the antioxidant pigment melanin and production of the antiphagocytic polysaccharide capsule. The bacterium also inhibited de novo cryptococcal biofilm formation but had only modest inhibitory effects on already formed biofilms or planktonic cell growth. The inhibition of fungal melanization was dependent on direct cell contact and live bacteria. B. safensis also had anti-virulence factor activity against another major human-associated fungal pathogen, Candida albicans Specifically, dual-species interaction studies revealed that the bacterium strongly inhibited C. albicans filamentation and biofilm formation. In particular, B. safensis physically attached to and degraded candidal filaments. Through genetic and phenotypic analyses, we demonstrated that bacterial chitinase activity against fungal cell wall chitin is a factor contributing to the antipathogen effect of B. safensisIMPORTANCE Pathogenic fungi are estimated to contribute to as many human deaths as tuberculosis or malaria. Two of the most common fungal pathogens, Cryptococcus neoformans and Candida albicans, account for up to 1.4 million infections per year with very high mortality rates. Few antifungal drugs are available for treatment, and development of novel therapies is complicated by the need for pathogen-specific targets. Therefore, there is an urgent need to identify novel drug targets and new drugs. Pathogens use virulence factors during infection, and it has recently been proposed that targeting these factors instead of the pathogen itself may represent a new approach to develop antimicrobials. Here, we identified a soil bacterium that specifically blocked virulence factor production and biofilm formation by C. neoformans and C. albicans We demonstrate that the bacterial antipathogen mechanism is based in part on targeting the fungal cell wall, a structure not found in human cells.

SUBMITTER: Mayer FL

PROVIDER: S-EPMC5626971 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Disarming Fungal Pathogens: Bacillus safensis Inhibits Virulence Factor Production and Biofilm Formation by Cryptococcus neoformans and Candida albicans.

Mayer François L FL Kronstad James W JW

mBio 20171003 5

Bacteria interact with each other in nature and often compete for limited nutrient and space resources. However, it is largely unknown whether and how bacteria also interact with human fungal pathogens naturally found in the environment. Here, we identified a soil bacterium, Bacillus safensis, which potently blocked several key Cryptococcus neoformans virulence factors, including formation of the antioxidant pigment melanin and production of the antiphagocytic polysaccharide capsul ...[more]

PMID: 28974618

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Project description:Heteroresistance to fluconazole (FLC) in Cryptococcus is a transient adaptive resistance which is lost upon release from the drug pressure. It is known that clones heteroresistant to FLC invariably contain disomic chromosomes, but how disomy is formed remains unclear. Previous reports suggested that the aneuploid heteroresistant colonies in Cryptococcus emerge from multinucleated cells, resembling the case in Candida albicans Although a small number of cells containing multiple nuclei appear in a short time after FLC treatment, we provide evidence that the heteroresistant colonies in the presence of FLC arise from uninucleate cells without involving multinuclear/multimeric stages. We found that fidelity of chromosome segregation in mitosis plays an important role in regulation of FLC heteroresistance frequency in C. neoformans Although FLC-resistant colonies occurred at a very low frequency, we were able to modulate the frequency of heteroresistance by overexpressing SMC1, which encodes a protein containing an SMC domain in chromosome segregation. Using time-lapse microscopy, we captured the entire process of colony formation from a single cell in the presence of FLC. All the multinucleated cells formed within a few hours of FLC exposure failed to multiply after a few cell divisions, and the cells able to proliferate to form colonies were all uninucleate without exception. Furthermore, no nuclear fusion event or asymmetric survival between mother and daughter cells, a hallmark of chromosome nondisjunction in haploid organisms, was observed. Therefore, the mechanisms of aneuploidy formation in C. neoformans appear different from most common categories of aneuploid formation known for yeasts.IMPORTANCE The gold standard of cryptococcosis treatment consists of induction therapy with amphotericin B followed by lifelong maintenance therapy with fluconazole (FLC). However, prolonged exposure to FLC induces the emergence of clones heteroresistant to azoles. All the heteroresistant clones thus far analyzed have been shown to be aneuploids, but how the aneuploid is formed remains unclear. Aneuploidy in fungi and other eukaryotic cells is known to result most commonly from chromosome missegregation during cell division due to defects in any one of the multiple components and processes that are required for the formation of two genetically identical daughter cells. Although formation of multinucleated cells has been observed in cells exposed to FLC, evidence for the emergence of drug-resistant aneuploid populations directly from such cells has been lacking. We show the evidence that the aneuploid in fluconazole-heteroresistant clones of Cryptococcus neoformans is derived neither from multinucleated cells nor from chromosome missegregation.

Project description:Abstract: Candida parapsilosis and Candida albicans are human fungal pathogens that belong to the CUG clade in the Saccharomycotina. In contrast to C. albicans, relatively little is known about the virulence properties of C. parapsilosis, a pathogen particularly associated with infections of premature neonates. We describe here the construction of >200 C. parapsilosis strains carrying double allele deletions of transcription factors, protein kinases and species-specific genes. Two independent deletions were constructed for each target gene. Growth in > 40 conditions was tested, including carbon source, temperature, and the presence of antifungal drugs. The phenotypes were compared to C. albicans strains with deletions of orthologous transcription factors. We found that many phenotypes are shared between the two species, such as the role of Upc2 as a regulator of azole resistance. Others are unique. For example, Cph2 plays a role in the hypoxic response in C. parapsilosis and not in C. albicans. We found extensive divergence between the biofilm regulators of the two species. We identified 7 transcription factors and one protein kinase that are required for biofilm development in C. parapsilosis. Only three (Efg1, Bcr1, and Ace2) have similar effects on C. albicans biofilms, whereas Cph2, Czf1, Gzf3 and Ume6 have major roles in C. parapsilosis only. In addition, two transcription factors (Brg1 and Tec1) with well-characterized roles in biofilm formation in C. albicans do not have the same function in C. parapsilosis. We also compared the transcription profile of C. parapsilosis and C. albicans biofilms. Our analysis suggests the processes shared between the two species are predominantly metabolic. C. parapsilosis mRNA profiles of wild type (WT) at 37 degree celcius in planktonic growth conditions and ace2-/-, cph2-/-, efg1-/-, czf1-/-, ume6-/-, bcr1-/- and WT in biofilm conditions were generated by deep sequencing, in triplicate, using Illumina HiSeq2000.

Dataset Information

Disarming Fungal Pathogens: Bacillus safensis Inhibits Virulence Factor Production and Biofilm Formation by Cryptococcus neoformans and Candida albicans.

Publications

Disarming Fungal Pathogens: <i>Bacillus safensis</i> Inhibits Virulence Factor Production and Biofilm Formation by <i>Cryptococcus neoformans</i> and <i>Candida albicans</i>.

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