The Rpd3 histone deacetylase is critical for temperature-mediated morphogenesis and virulence in the human fungal pathogen Histoplasma

Adaptive responses to environmental stimuli are integral to the survival and persistence of microbial pathogens. The thermally dimorphic human fungal pathogen Histoplasma senses temperature to transition between a mold form in soil and a pathogenic yeast in mammalian hosts. RYP transcription factors (TFs) are required to drive yeast-phase growth and the yeast transcriptome but the contributions of chromatin-modifying enzymes to the gene regulatory landscape of Histoplasma are unknown. Through chemical inhibition and genetics, we determined that the class I histone deacetylase (HDAC) RPD3 is required for normal Histoplasma yeast morphology at 37C. Rpd3 regulated the expression of key morphology-specific genes, including virulence genes critical for pathogenesis and TFs that drive filamentation, was required for normal DNA-binding activity of RYP TFs, and influenced histone acetylation levels at the loci of putative pro-filamentation TFs. Furthermore, Rpd3 was required for virulence in a macrophage model of infection. Taken together, Rpd3 is a critical regulatory component that both activates the pathogenesis program and represses the filamentation program to establish thermal dimorphism in Histoplasma.

对环境刺激的适应性应答是微生物病原体存活与持续定植的核心要素。热双态人类致病真菌——组织胞浆菌（Histoplasma）可感知温度变化，从而在土壤中的菌丝相与哺乳动物宿主内的致病酵母相之间发生形态转换。RYP转录因子（transcription factors, TFs）是驱动酵母相生长及酵母转录组构建的必需因子，但染色质修饰酶对组织胞浆菌基因调控网络的贡献尚不明确。本研究通过化学抑制与遗传学手段，证实I类组蛋白去乙酰化酶（histone deacetylase, HDAC）RPD3是组织胞浆菌在37℃下维持正常酵母形态的必需因子。Rpd3可调控关键形态特异性基因的表达，包括与致病过程密切相关的毒力基因以及促进菌丝形成的转录因子；其同时是维持RYP转录因子正常DNA结合活性的必需因子，并可影响潜在促菌丝形成转录因子基因位点的组蛋白乙酰化水平。此外，Rpd3是巨噬细胞感染模型中致病力维持的必需因子。综上，Rpd3是兼具激活致病程序与抑制菌丝形成程序的关键调控因子，可介导组织胞浆菌的热双态形态转换。