A Drug-Sensitive Genetic Network Masks Fungi from the Immune System 英文参考文献.docVIP

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A Drug-Sensitive Genetic Network Masks Fungi from the Immune System 英文参考文献.doc

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A Drug-Sensitive Genetic Network Masks Fungi from the Immune System 英文参考文献

ADrug-SensitiveGeneticNetworkMasksFungi fromtheImmuneSystem Robert T.Wheeler, Gerald R.Fink WhiteheadInstituteforBiomedicalResearch,Cambridge,Massachusetts,UnitedStatesofAmerica Fungal pathogens can be recognized by the immune system via their b-glucan, a potent proinflammatory molecule thatispresentathighlevelsbutispredominantlyburiedbeneathamannoproteincoatandinvisibletothehost.To investigatethenatureandsignificanceof‘‘masking’’thismolecule,wecharacterizedthemechanismofmaskingand consequencesofunmaskingforimmunerecognition.Wefoundthattheunderlyingb-glucaninthecellwallofCandida albicansisunmaskedbysubinhibitorydosesoftheantifungaldrugcaspofungin,causingtheexposedfungitoelicita stronger immune response. Using a library of bakers’ yeast (Saccharomyces cerevisiae) mutants, we uncovered a conserved genetic network that is required for concealing b-glucan from the immune system and limiting the host response.PerturbationofpartsofthisnetworkinthepathogenC.albicanscausedunmaskingofitsb-glucan,leading to increased b-glucan receptor-dependent elicitation of key proinflammatory cytokines from primary mouse macrophages. By creating an anti-inflammatory barrier to mask b-glucan, opportunistic fungi may promote commensalcolonizationandhaveanincreasedpropensityforcausingdisease.Targetingthewidelyconservedgene networkrequiredforcreatingandmaintainingthisbarriermayleadtonovelbroad-spectrumantimycotics. Citation:WheelerRT,FinkGR(2006)Adrug-sensitivegeneticnetworkmasksfungifromtheimmunesystem.PLoSPathog2(4):e35.DOI:10.1371/journal.ppat.0020035 subinhibitory concentrations of the antifungal drug caspo- funginexposesthenormallymaskedb-glucan.Wealsode?ne Introduction The innate immune system recognizes microbes based on theirpathogen-associatedmolecularpatterns(PAMPs),which provoke pathogen-speci?c responses tailored to meet the challenge [1]. This ensures that parasites, viruses, bacteria, and fungi are each attacked appropriately. Fungi are opportunistic pathogens responsible f