Mp1p homologues as virulence factors in Aspergillus fumigatus

Recently, we showed that Mp1p is an important virulence factor of Talaromyces marneffei, a dimorphic fungus phylogenetically closely related to Aspergillus fumigatus. In this study, we investigated the virulence properties of the four Mp1p homologues (Afmp1p, Afmp2p, Afmp3p, and Afmp4p) in A. fumigatus using a mouse model. All mice died 7 days after challenge with wild-type A. fumigatus QC5096, AFMP1 knockdown mutant, AFMP2 knockdown mutant and AFMP3 knockdown mutant and 28 days after challenge with AFMP4 knockdown mutant (P<.0001). Only 11% of mice died 30 days after challenge with AFMP1-4 knockdown mutant (P<.0001). For mice challenge with AFMP1-4 knockdown mutant, lower abundance of fungal elements was observed in brains, kidneys, and spleens compared to mice challenge with QC5096 at day 4 post-infection. Fungal counts in brains of mice challenge with QC5096 or AFMP4 knockdown mutant were significantly higher than those challenge with AFMP1-4 knockdown mutant (P<.01 and P<.05). Fungal counts in kidneys of mice challenge with QC5096 or AFMP4 knockdown mutant were significantly higher than those challenge with AFMP1-4 knockdown mutant (P<.001 and P<.001) and those of mice challenge with QC5096 were significantly higher than those challenge with AFMP4 knockdown mutant (P<.05). There is no difference among the survival rates of wild-type A. fumigatus, AFMP4 knockdown mutant and AFMP1-4 knockdown mutant, suggesting that Mp1p homologues in A. fumigatus do not mediate its virulence via improving its survival in macrophage as in the case in T. marneffei. Afmp1p, Afmp2p, Afmp3p, and Afmp4p in combination are important virulence factors of A. fumigatus.

[1]  P. Woo,et al.  Talaromyces marneffei Mp1p Is a Virulence Factor that Binds and Sequesters a Key Proinflammatory Lipid to Dampen Host Innate Immune Response. , 2017, Cell chemical biology.

[2]  K. Yuen,et al.  Mp1p Is a Virulence Factor in Talaromyces (Penicillium) marneffei , 2016, PLoS neglected tropical diseases.

[3]  O. Kniemeyer,et al.  Identification and Characterization of a Novel Aspergillus fumigatus Rhomboid Family Putative Protease, RbdA, Involved in Hypoxia Sensing and Virulence , 2016, Infection and Immunity.

[4]  J. Chan,et al.  Genetic diversity of Aspergillus species isolated from onychomycosis and Aspergillus hongkongensis sp. nov., with implications to antifungal susceptibility testing. , 2016, Diagnostic microbiology and infectious disease.

[5]  G. Goldman,et al.  The Aspergillus fumigatus sitA Phosphatase Homologue Is Important for Adhesion, Cell Wall Integrity, Biofilm Formation, and Virulence , 2015, Eukaryotic Cell.

[6]  G. Goldman,et al.  High osmolarity glycerol response PtcB phosphatase is important for Aspergillus fumigatus virulence , 2015, Molecular microbiology.

[7]  E. Werner,et al.  ChIP-seq and In Vivo Transcriptome Analyses of the Aspergillus fumigatus SREBP SrbA Reveals a New Regulator of the Fungal Hypoxia Response and Virulence , 2014, PLoS pathogens.

[8]  P. Woo,et al.  The biosynthetic pathway for a thousand-year-old natural food colorant and citrinin in Penicillium marneffei , 2014, Scientific Reports.

[9]  Avner Schlessinger,et al.  PredictProtein—an open resource for online prediction of protein structural and functional features , 2014, Nucleic Acids Res..

[10]  K. Yuen,et al.  Misidentification of Aspergillus nomius and Aspergillus tamarii as Aspergillus flavus: Characterization by Internal Transcribed Spacer, β-Tubulin, and Calmodulin Gene Sequencing, Metabolic Fingerprinting, and Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry , 2014, Journal of Clinical Microbiology.

[11]  P. Woo,et al.  Proteome profiling of the dimorphic fungus Penicillium marneffei extracellular proteins and identification of glyceraldehyde‐3‐phosphate dehydrogenase as an important adhesion factor for conidial attachment , 2013, The FEBS journal.

[12]  R. A. Cramer,et al.  Dsc Orthologs Are Required for Hypoxia Adaptation, Triazole Drug Responses, and Fungal Virulence in Aspergillus fumigatus , 2012, Eukaryotic Cell.

[13]  K. Yuen,et al.  First Discovery of Two Polyketide Synthase Genes for Mitorubrinic Acid and Mitorubrinol Yellow Pigment Biosynthesis and Implications in Virulence of Penicillium marneffei , 2012, PLoS neglected tropical diseases.

[14]  M. Nei,et al.  MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. , 2011, Molecular biology and evolution.

[15]  S. Brunak,et al.  SignalP 4.0: discriminating signal peptides from transmembrane regions , 2011, Nature Methods.

[16]  James J. Cai,et al.  High diversity of polyketide synthase genes and the melanin biosynthesis gene cluster in Penicillium marneffei , 2010, The FEBS journal.

[17]  Hubertus Haas,et al.  HapX-Mediated Adaption to Iron Starvation Is Crucial for Virulence of Aspergillus fumigatus , 2010, PLoS pathogens.

[18]  E. Espeso,et al.  Identification of possible targets of the Aspergillus fumigatus CRZ1 homologue, CrzA , 2010, BMC Microbiology.

[19]  Martin Bard,et al.  A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus , 2008, PLoS pathogens.

[20]  C. Cooper,et al.  Insights into the pathogenicity of Penicillium marneffei. , 2008, Future microbiology.

[21]  Ken Haynes,et al.  Distinct Roles for Intra- and Extracellular Siderophores during Aspergillus fumigatus Infection , 2007, PLoS pathogens.

[22]  Miguel Ángel Díaz Moreno,et al.  The regulation of zinc homeostasis by the ZafA transcriptional activator is essential for Aspergillus fumigatus virulence , 2007, Molecular microbiology.

[23]  Haomiao Ouyang,et al.  Glycosylphosphatidylinositol (GPI) anchor is required in Aspergillus fumigatus for morphogenesis and virulence , 2007, Molecular microbiology.

[24]  D. Nickle,et al.  Molecular Studies Reveal Frequent Misidentification of Aspergillus fumigatus by Morphotyping , 2006, Eukaryotic Cell.

[25]  K. Yuen,et al.  A novel approach for screening immunogenic proteins in Penicillium marneffei using the ΔAFMP1ΔAFMP2 deletion mutant of Aspergillus fumigatus , 2006 .

[26]  William R. Kirkpatrick,et al.  Calcineurin Controls Growth, Morphology, and Pathogenicity in Aspergillus fumigatus , 2006, Eukaryotic Cell.

[27]  P. Woo,et al.  A novel approach for screening immunogenic proteins in Penicillium marneffei using the DeltaAFMP1DeltaAFMP2 deletion mutant of Aspergillus fumigatus. , 2006, FEMS microbiology letters.

[28]  M. Moore,et al.  The Aspergillus fumigatus Siderophore Biosynthetic Gene sidA, Encoding l-Ornithine N5-Oxygenase, Is Required for Virulence , 2005, Infection and Immunity.

[29]  A. Beauvais,et al.  Deletion of GEL2 encoding for a β(1–3)glucanosyltransferase affects morphogenesis and virulence in Aspergillus fumigatus , 2005, Molecular microbiology.

[30]  A. Dougall,et al.  Multiple Genetically Distinct Groups Revealed among Clinical Isolates Identified as Atypical Aspergillus fumigatus , 2005, Journal of Clinical Microbiology.

[31]  A. Brakhage,et al.  The Cyclic AMP-Dependent Protein Kinase A Network Regulates Development and Virulence in Aspergillus fumigatus , 2004, Infection and Immunity.

[32]  E. Mylonakis,et al.  Disruption of the Aspergillus fumigatus Gene Encoding Nucleolar Protein CgrA Impairs Thermotolerant Growth and Reduces Virulence , 2004, Infection and Immunity.

[33]  P. Woo,et al.  AFMP2 Encodes a Novel Immunogenic Protein of the Antigenic Mannoprotein Superfamily in Aspergillus fumigatus , 2004, Journal of Clinical Microbiology.

[34]  Samson S. Y. Wong,et al.  The mitochondrial genome of the thermal dimorphic fungus Penicillium marneffei is more closely related to those of molds than yeasts , 2003, FEBS letters.

[35]  B. Jahn,et al.  cAMP signaling in Aspergillus fumigatus is involved in the regulation of the virulence gene pksP and in defense against killing by macrophages , 2003, Molecular Genetics and Genomics.

[36]  K. Yuen,et al.  AFLMP1 Encodes an Antigenic Cell Wall Protein in Aspergillus flavus , 2003, Journal of Clinical Microbiology.

[37]  P. Woo,et al.  Detection of Cell Wall Galactomannoprotein Afmp1p in Culture Supernatants of Aspergillus fumigatus and in Sera of Aspergillosis Patients , 2002, Journal of Clinical Microbiology.

[38]  Søren Brunak,et al.  Prediction of Glycosylation Across the Human Proteome and the Correlation to Protein Function , 2001, Pacific Symposium on Biocomputing.

[39]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[40]  K. Yuen,et al.  Characterization of AFMP1: a Novel Target for Serodiagnosis of Aspergillosis , 2001, Journal of Clinical Microbiology.

[41]  P Bork,et al.  Automated annotation of GPI anchor sites: case study C. elegans. , 2000, Trends in biochemical sciences.

[42]  Computer Corner,et al.  Automated annotation of GPI anchor sites: case study , 2000 .

[43]  J. Latgé,et al.  Aspergillus fumigatus and Aspergillosis , 1999, Clinical Microbiology Reviews.

[44]  R D Appel,et al.  Protein identification and analysis tools in the ExPASy server. , 1999, Methods in molecular biology.

[45]  K. Yuen,et al.  MP1 Encodes an Abundant and Highly Antigenic Cell Wall Mannoprotein in the Pathogenic Fungus Penicillium marneffei , 1998, Infection and Immunity.

[46]  K. Yuen,et al.  Stage-specific manifestation of mold infections in bone marrow transplant recipients: risk factors and clinical significance of positive concentrated smears. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.