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Abstract
Author SummaryMicrobial pathogens of humans display the ability to thrive at host temperature. So-called “thermally dimorphic” fungal pathogens, which include Histoplasma capsulatum, are a class of soil fungi that upon being inhaled into the human lung, undergo dramatic changes in cell shape and virulence gene expression in response to host temperature. The ability of these pathogens to cause disease is exquisitely coupled to temperature response. Here we elucidate the regulatory network that governs the ability of H. capsulatum to switch from a filamentous form in the soil environment to a pathogenic yeast form at body temperature. The circuit is driven by three transcription regulators (Ryp1, Ryp2, and Ryp3) that control yeast-phase growth. We show that these factors, which include two highly conserved proteins of the Velvet family of unknown function, bind to specific regulatory DNA elements and directly regulate expression of virulence genes. We identify and characterize Ryp4, a fourth regulator of this pathway, and define DNA motifs that recruit these transcription factors to their temperature-responsive target genes. Our results provide a molecular understanding of how changes in cell shape are linked to expression of virulence genes in thermally dimorphic fungi.
Highlights
Cells adapt to their environment by responding to specific environmental stimuli such as light, temperature, and nutrients
We performed whole-genome expression profiling experiments comparing the transcriptional profiles of multiple biological replicates of ryp1, ryp2, ryp3 mutants and wild-type strains grown at room temperature (RT) and 37uC
We identified 388 genes with significantly increased transcript levels and 376 genes with significantly decreased transcript levels in wild-type yeast cells grown at 37uC compared to wild-type filaments grown at RT (Figure 1A and Table S1)
Summary
Cells adapt to their environment by responding to specific environmental stimuli such as light, temperature, and nutrients. Mammalian body temperature can signal the induction of pathways required for host colonization and pathogenesis [1] One such group of organisms is the thermally dimorphic fungal pathogens, which include Coccidioides, Paracoccidioides, Blastomyces, and Histoplasma species. These evolutionarily related fungi are notable among fungal pathogens in that they all cause disease in healthy individuals [2]. Each of these organisms grows in a mold form in the soil, forming long, connected filaments that produce vegetative spores [3]. For all thermally dimorphic fungi, host temperature is the key signal that triggers this developmental switch, but little is known about the coordinated induction of morphologic changes and virulence gene expression by temperature
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