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      Candida albicans Infection of Caenorhabditis elegans Induces Antifungal Immune Defenses

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          Abstract

          Candida albicans yeast cells are found in the intestine of most humans, yet this opportunist can invade host tissues and cause life-threatening infections in susceptible individuals. To better understand the host factors that underlie susceptibility to candidiasis, we developed a new model to study antifungal innate immunity. We demonstrate that the yeast form of C. albicans establishes an intestinal infection in Caenorhabditis elegans, whereas heat-killed yeast are avirulent. Genome-wide, transcription-profiling analysis of C. elegans infected with C. albicans yeast showed that exposure to C. albicans stimulated a rapid host response involving 313 genes (124 upregulated and 189 downregulated, ∼1.6% of the genome) many of which encode antimicrobial, secreted or detoxification proteins. Interestingly, the host genes affected by C. albicans exposure overlapped only to a small extent with the distinct transcriptional responses to the pathogenic bacteria Pseudomonas aeruginosa or Staphylococcus aureus, indicating that there is a high degree of immune specificity toward different bacterial species and C. albicans. Furthermore, genes induced by P. aeruginosa and S. aureus were strongly over-represented among the genes downregulated during C. albicans infection, suggesting that in response to fungal pathogens, nematodes selectively repress the transcription of antibacterial immune effectors. A similar phenomenon is well known in the plant immune response, but has not been described previously in metazoans. Finally, 56% of the genes induced by live C. albicans were also upregulated by heat-killed yeast. These data suggest that a large part of the transcriptional response to C. albicans is mediated through “pattern recognition,” an ancient immune surveillance mechanism able to detect conserved microbial molecules (so-called pathogen-associated molecular patterns or PAMPs). This study provides new information on the evolution and regulation of the innate immune response to divergent pathogens and demonstrates that nematodes selectively mount specific antifungal defenses at the expense of antibacterial responses.

          Author Summary

          Despite being a part of the normal flora of healthy individuals, Candida albicans is the most common fungal pathogen of humans and can cause infections that are associated with staggeringly high mortality rates. Here we devise a model for the study of the host immune response to C. albicans infection using the nematode C. elegans. We found that infection with the yeast form of C. albicans induces rapid and robust transcriptional changes in C. elegans. Analyses of these differentially regulated genes indicate that the nematode mounts antifungal defenses that are remarkably distinct from the host responses to pathogenic bacteria and that the nematode recognizes components possessed by heat-killed C. albicans to initiate this response. Interestingly, during infection with a pathogenic fungus, the nematode downregulates antibacterial immune response genes, which may reflect an evolutionary tradeoff between bacterial and fungal defense.

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          Most cited references69

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          DAVID: Database for Annotation, Visualization, and Integrated Discovery.

          Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.
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            daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans.

            A C. elegans neurosecretory signaling system regulates whether animals enter the reproductive life cycle or arrest development at the long-lived dauer diapause stage. daf-2, a key gene in the genetic pathway that mediates this endocrine signaling, encodes an insulin receptor family member. Decreases in DAF-2 signaling induce metabolic and developmental changes, as in mammalian metabolic control by the insulin receptor. Decreased DAF-2 signaling also causes an increase in life-span. Life-span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism, diapause, and longevity.
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              Nonfilamentous C. albicans mutants are avirulent.

              Candida albicans and Saccharomyces cerevisiae switch from a yeast to a filamentous form. In Saccharomyces, this switch is controlled by two regulatory proteins, Ste12p and Phd1p. Single-mutant strains, ste12/ste12 or phd1/phd1, are partially defective, whereas the ste12/ste12 phd1/phd1 double mutant is completely defective in filamentous growth and is noninvasive. The equivalent cph1/cph1 efg1/efg1 double mutant in Candida (Cph1p is the Ste12p homolog and Efg1p is the Phd1p homolog) is also defective in filamentous growth, unable to form hyphae or pseudohyphae in response to many stimuli, including serum or macrophages. This Candida cph1/cph1 efg1/efg1 double mutant, locked in the yeast form, is avirulent in a mouse model.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                June 2011
                June 2011
                23 June 2011
                : 7
                : 6
                : e1002074
                Affiliations
                [1 ]Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [2 ]Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [3 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
                [4 ]Harvard Medical School, Boston, Massachusetts, United States of America
                University of Massachusetts Medical School, United States of America
                Author notes

                Conceived and designed the experiments: RPW FMA EM. Performed the experiments: RPW. Analyzed the data: RPW. Contributed reagents/materials/analysis tools: RPW. Wrote the paper: RPW FMA EM.

                Article
                PPATHOGENS-D-10-00220
                10.1371/journal.ppat.1002074
                3121877
                21731485
                bde20c73-d723-452b-8b16-10681c5b7611
                Pukkila-Worley et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 27 October 2010
                : 6 April 2011
                Page count
                Pages: 13
                Categories
                Research Article
                Biology
                Immunology
                Immunity
                Innate Immunity
                Model Organisms
                Animal Models
                Caenorhabditis Elegans
                Yeast and Fungal Models
                Candida Albicans
                Medicine
                Infectious Diseases
                Fungal Diseases
                Mycosis

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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