Self-Regulation of Candida albicans Population Size during GI Colonization

Department of Molecular Biology and Microbiology, Tufts University, Boston, Massachusetts, United States of America.
PLoS Pathogens (Impact Factor: 7.56). 01/2008; 3(12):e184. DOI: 10.1371/journal.ppat.0030184
Source: PubMed


Interactions between colonizing commensal microorganisms and their hosts play important roles in health and disease. The opportunistic fungal pathogen Candida albicans is a common component of human intestinal flora. To gain insight into C. albicans colonization, genes expressed by fungi grown within a host were studied. The EFH1 gene, encoding a putative transcription factor, was highly expressed during growth of C. albicans in the intestinal tract. Counterintuitively, an efh1 null mutant exhibited increased colonization of the murine intestinal tract, a model of commensal colonization, whereas an EFH1 overexpressing strain exhibited reduced colonization of the intestinal tract and of the oral cavity of athymic mice, the latter situation modeling human mucosal candidiasis. When inoculated into the bloodstream of mice, both efh1 null and EFH1 overexpressing strains caused lethal infections. In contrast, other mutants are attenuated in virulence following intravenous inoculation but exhibited normal levels of intestinal colonization. Finally, although expression of several genes is dependent on transcription factor Efg1p during laboratory growth, Efg1p-independent expression of these genes was observed during growth within the murine intestinal tract. These results show that expression of EFH1 regulated the level of colonizing fungi, favoring commensalism as opposed to candidiasis. Also, different genes are required in different host niches and the pathway(s) that regulates gene expression during host colonization can differ from well-characterized pathways used during laboratory growth.

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Available from: Malcolm Whiteway, Oct 01, 2015
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    • "To achieve efficient gastrointestinal colonization, this fungus possesses complicated adaptation capacities to sense host niches, adhere to the host mucosal surface and successfully colonize this unique environment. All of these capacities are also related to morphogenetic processes (White et al., 2007). Therefore, strategies that inhibit morphogenesis of this fungus may also have an impact on relevant physiological processes, such as adhesion, colonization and invasion of host tissues, and may be used for antifungal drugs against its infections. "
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    ABSTRACT: Candida albicans morphogenesis and gastrointestinal (GI) colonization are closely associated with the pathogenicity of this pathogen. This study investigated the in vitro and in vivo effect of verapamil, a calcium channel blocker, on these processes. Exposure to ≥10 μg mL–1 verapamil led to a significant decrease of C. albicans hyphal cells. The ability to adhere to a polystyrene surface and buccal epithelial cells was inhibited by exposure to ≥20 μg mL–1 verapamil. Detection of the Hwp1–green fluorescent protein fusion protein showed that verapamil inhibited expression and transport of Hwp1, indicating its activity against both the regulation network of morphogenesis-associated proteins and the secretory pathway in C. albicans. Moreover, treatment with verapamil at 10 mg (–1 led to a remarkable decrease in GI-colonizing fungal cells. This study revealed the inhibitory effect of verapamil on C. albicans hyphal development, adhesion and GI colonization, which is relevant to decreased expression and abnormal transport of the proteins required for morphogenesis. Therefore, verapamil may be taken into account when choosing an antifungal therapy against C. albicans colonization and infection.This article is protected by copyright. All rights reserved.
    FEMS Yeast Research 03/2014; 14(4). DOI:10.1111/1567-1364.12150 · 2.82 Impact Factor
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    • "An unbalanced microflora and a malfunctioning immune system are unable to control the C. albicans population size and the host becomes susceptible to candidiasis (Macphail et al., 2002; Perlroth et al., 2007). In these situations, the fungal burden increases and various environmental cues, such as nutrient availability, pH, and temperature stimulate hypha formation (Biswas et al., 2007; Whiteway and Bachewich, 2007; Shapiro and Cowen, 2010; Sudbery, 2011). This may lead to life-threatening infections where the fungi disseminate to different internal organs (Macphail et al., 2002; Pfaller and Diekema, 2007). "
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    ABSTRACT: A range of attributes determines the virulence of human pathogens. During interactions with their hosts, pathogenic microbes often undergo transitions between distinct stages, and the ability to switch between these can be directly related to the disease process. Understanding the mechanisms and dynamics of these transitions is a key factor in understanding and combating infectious diseases. The human fungal pathogen Candida albicans exhibits different morphotypes at different stages during the course of infection (candidiasis). For example, hyphae are considered to be the invasive form, which causes tissue damage, while yeast cells are predominant in the commensal stage. Here, we described interactions of C. albicans with its human host in a game theoretic model. In the game, players are fungal cells. Each fungal cell can adopt one of the two strategies: to exist as a yeast or hyphal cell. We characterized the ranges of model parameters in which the coexistence of both yeast and hyphal forms is plausible. Stability analysis of the system showed that, in theory, a reduced ability of the host to specifically recognize yeast and hyphal cells can result in bi-stability of the microbial populations' profile. Inspired by the model analysis we reasoned that the types of microbial interactions can change during invasive candidiasis. We found that positive cooperation among fungal cells occurs in mild infections and an enhanced tendency to invade the host is associated with negative cooperation. The model can easily be extended to multi-player systems with direct application to identifying individuals that enhance either positive or negative cooperation. Results of the modeling approach have potential application in developing treatment strategies.
    Frontiers in Microbiology 02/2014; 5:41. DOI:10.3389/fmicb.2014.00041 · 3.99 Impact Factor
    • "These models make use of either neonatal or adult immunocompromised mice or animals partially depleted in the gastrointestinal microbiota by the use of a broad spectrum antibiotic therapy [15]. Combined genetics and transcriptional analyses have revealed the role of certain metabolic traits [16], transcription factors [17], [18] and phenotypic switch-related genes [19] in the adaptation to the gastrointestinal niche. "
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    ABSTRACT: The opportunistic pathogen Candida albicans is a frequent inhabitant of the human gastrointestinal tract where it usually behaves as a harmless commensal. In this particular niche, it needs to adapt to the different micro environments that challenge its survival within the host. In order to determine those factors involved in gut adaptation, we have used a gastrointestinal model of colonization in mouse to trace the behaviour of fungal cells. We have developed a genetic labelling system based on the complementary spectral properties of the fluorescent proteins GFP and a new C. albicans codon-adapted RFP (dTOM2) that allow a precise quantification of the fungal population in the gut via standard in vitro cultures or flow cytometry. This methodology has allowed us to determine the role of the three MAP kinase pathways of C. albicans (mediated by the MAPK Mkc1, Cek1 or Hog1) in mouse gut colonization via competitive assays with MAPK pathway mutants and their isogenic wild type strain. This approach reveals the signalling through HOG pathway as a critical factor influencing the establishment of C. albicans in the mouse gut. Less pronounced effects for mkc1 or cek1 mutants were found, only evident after 2-3 weeks of colonization. We have also seen that hog1 mutants is defective in adhesion to the gut mucosa and sensitive to bile salts. Finally, we have developed a genetic strategy for the in vivo excision (tetracycline-dependent) of any specific gene during the course of colonization in this particular niche, allowing the analysis of its role during gut colonization.
    PLoS ONE 01/2014; 9(1):e87128. DOI:10.1371/journal.pone.0087128 · 3.23 Impact Factor
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