MAP kinases and phosphatases are the main signaling pathways of tolerance to different kinds of stresses in eukaryotes. The multifactorial nature of A. fumigatus virulence and pathogenicity program in the mammalian host places the response to different kinds of stresses as one of the most important responses in the process of establishment of this organism as a pathogen. These signaling pathways are important for the cell wall biosynthesis and remodeling, responses to oxidative stress and antifungal drugs, biofilm formation and adhesion, and possibly other essential features not yet investigated such as, blood dissemination from the pulmonary epithelium and strategies of immunological evasion. The understanding of the metabolic nets that are coordinated by MAP kinases will provide an opportunity for the construction of the signaling pathways that are important for stress tolerance and the establishment of the A. fumigatus virulence and pathogenicity program in mammals. Thus, the main objectives of this project are: (i) the identification of specific transcription factors that are activated by different kinds of stress and that are dependent on MAP kinases; (ii) the identification of proteins that interact physically with the MAP kinases when A. fumigatus is exposed to different kinds of stresses; (iii) the investigation of a possible "crosstalk" among the different A. fumigatus MAP kinases during different kinds of stresses; (iv) the molecular characterization of MpkB and the verification if this MAP kinase is important for A. fumigatus virulence, and (v) the characterization of the interaction between the A. fumigatus mutants generated in this study and the immunosupressed and imunocompetent murine hosts.
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