title: PrtT-regulated proteins secreted by Aspergillus fumigatus activate MAPK signaling in exposed A549 lung cells leading to necrotic cell death.
abstract: Aspergillus fumigatus is the most commonly encountered mold pathogen of humans, predominantly infecting the respiratory system. Colonization and penetration of the lung alveolar epithelium is a key but poorly understood step in the infection process. This study focused on identifying the transcriptional and cell-signaling responses activated in A549 alveolar carcinoma cells incubated in the presence of A. fumigatus wild-type and ΔPrtT protease-deficient germinating conidia and culture filtrates (CF). Microarray analysis of exposed A549 cells identified distinct classes of genes whose expression is altered in the presence of germinating conidia and CF and suggested the involvement of both NFkB and MAPK signaling pathways in mediating the cellular response. Phosphoprotein analysis of A549 cells confirmed that JNK and ERK1/2 are phosphorylated in response to CF from wild-type A. fumigatus and not phosphorylated in response to CF from the ΔPrtT protease-deficient strain. Inhibition of JNK or ERK1/2 kinase activity substantially decreased CF-induced cell damage, including cell peeling, actin-cytoskeleton damage, and reduction in metabolic activity and necrotic death. These results suggest that inhibition of MAPK-mediated host responses to treatment with A. fumigatus CF decreases cellular damage, a finding with possible clinical implications.
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, Israel. nosherov@post.tau.ac.il
authors.forename: Haim
authors.initials: H
authors.lastname: Sharon
authors.forename: David
authors.initials: D
authors.lastname: Amar
authors.forename: Emma
authors.initials: E
authors.lastname: Levdansky
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mircus
authors.forename: Yana
authors.initials: Y
authors.lastname: Shadkchan
authors.forename: Ron
authors.initials: R
authors.lastname: Shamir
authors.forename: Nir
authors.initials: N
authors.lastname: Osherov
mesh_terms: D000199:Actins / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005374:Filtration; D005656:Fungal Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009336:Necrosis / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000378:metabolism; D058105:Polymerization / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015203:Reproducibility of Results; D013172:Spores, Fungal / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000199:Actins; D016207:Cytokines; D005656:Fungal Proteins; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D010447:Peptide Hydrolases