This may explain why the pathological manifestation in lung and kidney was modest our study

l of all organisms. In particular, the heat shock response is a fundamentally important process that has been highly conserved from yeasts to humans. In response to a sudden and acute temperature up-shift, cells rapidly induce the expression of genes that encode molecular chaperones, proteases and other classes of protein. These proteins function in the synthesis, folding, maturation, trafficking and degradation of proteins, and are order 300817-68-9 essential for protection against, and recovery from the cellular damage associated with the presence of the aberrantly folded proteins generated by the heat shock. In eukaryotic cells the expression of heat shock protein genes is controlled by the heat shock transcription factor, which is evolutionarily conserved from Saccharomyces cerevisiae to humans. S. cerevisiae Hsf1 is an essential protein that binds to heat shock elements in the promoter regions of target genes, which include HSP genes. Hsf1 activation leads to the up-regulation of these target genes in response to heat shock thereby promoting cellular adaptation to the thermal insult. The major fungal pathogen of humans, Candida albicans, has retained a heat shock response, even though this yeast is obligately associated with warm-blooded animals. Like S. cerevisiae, HSP gene activation in C. albicans is mediated by an essential, evolutionarily conserved heat shock transcription factor, Hsf1. It is thought that, via this heat shock regulon, C. albicans cells tune the levels of essential chaperones to their ambient growth temperature. C. albicans appears to be well adapted to its human host. 10455325 It exists ” as a relatively harmless commensal organism within the microbial flora of the oral and gastrointestinal tracts in many individuals. However, it often causes mucosal infections in otherwise healthy individuals, and can instigate lifethreatening systemic infections in immunocompromised patients. Indeed, approximately 40% of haematogenously disseminated Candida infections are fatal in some patient groups. Historically, the heat shock response in C. albicans has been of interest for a number of reasons. First, temperature up-shifts promote morphological transitions from the yeast to hyphal growth forms, and this cellular morphogenesis is a major virulence trait in C. albicans. Second, mutations that block Hsf1 activation in C. albicans prevent thermal adaptation and significantly reduce the virulence of this major pathogen. Third, antifungal drug resistance is abrogated both by Hsp90 inhibitors and by elevated temperatures equivalent to those in febrile patients. Fourth, C. albicans heat shock proteins are immunogenic, thereby directly affecting host-pathogen interactions during infection. Finally, autoantibodies against Hsp90 are immunoprotective against C. albicans infections. Taken together, the heat shock response of fungal pathogens is of fundamental importance because it is essential for virulence, and because heat shock proteins represent targets for novel therapeutic strategies. Autoregulation of Thermal Adaptation The exact mechanisms by which thermal adaptation is regulated in eukaryotic cells have been extensively studied, but are still not yet fully understood. When human cells are exposed to heat or a chemical stress, protein unfolding increases, and nonnative proteins begin to accumulate. These non-native proteins are believed to compete with HSF1 for binding to Hsp90, resulting in an increase in unbound HSF1 molecules which rapidly trimerize.