Drosophila melanogaster Thor and Response to Candida albicans Infection

Genetics Group, Biotechnology Research Institute, National Research Council, Montreal, Quebec H4P 2R2, Canada.
Eukaryotic Cell (Impact Factor: 3.18). 05/2007; 6(4):658-63. DOI: 10.1128/EC.00346-06
Source: PubMed


We used Drosophila melanogaster macrophage-like Schneider 2 (S2) cells as a model to study cell-mediated innate immunity against infection by the opportunistic
fungal pathogen Candida albicans. Transcriptional profiling of S2 cells coincubated with C. albicans cells revealed up-regulation of several genes. One of the most highly up-regulated genes during this interaction is the D. melanogaster translational regulator 4E-BP encoded by the Thor gene. Analysis of Drosophila 4E-BPnull mutant survival upon infection with C. albicans showed that 4E-BP plays an important role in host defense, suggesting a role for translational control in the D. melanogaster response to C. albicans infection.

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Available from: Paul F. Lasko, Oct 06, 2015
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    • "A high-throughput screen in Drosophila melanogaster S2 RNAi library identified a novel protein, macroglobulin complement related (Mcr), that exerts opsonizing activity specifically against Candida albicans [33]. In addition, S2 Drosophila cells efficiently eliminate C. albicans yeast cells and induce significant damage to the hyphae of filamentous fungi, including Aspergillus and the Mucorales, in a way that resembles the antifungal effector function of human phagocytes [23, 34]. "
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    ABSTRACT: Airborne opportunistic fungi, including Aspergillus and other less common saprophytic molds, have recently emerged as important causes of mortality in immunocompromised individuals. Understanding the molecular mechanisms of host-fungal interplay in robust experimental pathosystems is becoming a research priority for development of novel therapeutics to combat these devastating infections. Over the past decade, invertebrate hosts with evolutionarily conserved innate immune signaling pathways and powerful genetics, such as Drosophila melanogaster, have been employed as a means to overcome logistic restrains associated with the use mammalian models of fungal infections. Recent studies in Drosophila models of filamentous fungi demonstrated that several genes implicated in fungal virulence in mammals also play a similarly important pathogenic role in fruit flies, and important host-related aspects in fungal pathogenesis are evolutionarily conserved. In view of recent advances in Drosophila genetics, fruit flies will become an invaluable surrogate model to study immunopathogenesis of fungal diseases.
    International Journal of Microbiology 02/2012; 2012:583792. DOI:10.1155/2012/583792
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    • "Also, in addition to causing tissue damage, the induced expression of Sap2 may lead to the degradation of extracellular signaling components important for energy homeostasis or the host immune response like secreted antimicrobial peptides (AMPs). In fact, it has been shown that Drosophila genes involved in protein translation, energy homeostasis, and stress responses are important for the host to survive an infection [57], [58], [59]. Thus, while it is likely that less tissue damage caused by infection is the primary reason flies survive infection with stp1Δ compared to wild type C. albicans, it is possible that stp1Δ mutants may fail to interfere with the other facets of the host's ability to survive infection. "
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    ABSTRACT: The fungal pathogen Candida albicans is a common cause of opportunistic infections in humans. We report that wild-type Drosophila melanogaster (OrR) flies are susceptible to virulent C. albicans infections and have established experimental conditions that enable OrR flies to serve as model hosts for studying C. albicans virulence. After injection into the thorax, wild-type C. albicans cells disseminate and invade tissues throughout the fly, leading to lethality. Similar to results obtained monitoring systemic infections in mice, well-characterized cph1Δ efg1Δ and csh3Δ fungal mutants exhibit attenuated virulence in flies. Using the OrR fly host model, we assessed the virulence of C. albicans strains individually lacking functional components of the SPS sensing pathway. In response to extracellular amino acids, the plasma membrane localized SPS-sensor (Ssy1, Ptr3, and Ssy5) activates two transcription factors (Stp1 and Stp2) to differentially control two distinct modes of nitrogen acquisition (host protein catabolism and amino acid uptake, respectively). Our results indicate that a functional SPS-sensor and Stp1 controlled genes required for host protein catabolism and utilization, including the major secreted aspartyl protease SAP2, are required to establish virulent infections. By contrast, Stp2, which activates genes required for amino acid uptake, is dispensable for virulence. These results indicate that nutrient availability within infected hosts directly influences C. albicans virulence.
    PLoS ONE 11/2011; 6(11):e27434. DOI:10.1371/journal.pone.0027434 · 3.23 Impact Factor
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    • "Using the live Drosophila model, Thor was found to be involved in fly survival in response to Candida infection, suggesting a significant component of the fruit fly's cell-based immunity may involve regulation of translation (Fig. 2) (Levitin et al., 2007). This validation of the results derived from Drosophila macrophage-like cells by using the whole fly helps to confirm S2 cells as a useful model to study Drosophila– Candida interactions (Levitin et al., 2007). "
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    ABSTRACT: The fruit fly Drosophila melanogaster is an important model for the analysis of the interaction between host immune systems and fungal pathogens. Recent experiments have extended our understanding of the Toll-based signalling pathway critical to response to fungal infections, and identified new elements involved in cellular and humoral-based defences. The fly immune system shows remarkable sophistication in its ability to discriminate among pathogens, and the powerful genetics available to researchers studying the adult fly response, and the ability to manipulate cultured phagocytic cell lines with RNAi, are allowing researchers to dissect the molecular details of the process.
    Cellular Microbiology 06/2008; 10(5):1021-6. DOI:10.1111/j.1462-5822.2008.01120.x · 4.92 Impact Factor
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