Transcriptional regulation of A. fumigatus virulence

烟曲霉毒力的转录调控

• 批准号: 7414750
• 负责人: Scott G Filler
• 金额: $ 31.07万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414750
• 关键词: Alveolus; Animals; Apoptosis; Aspergillosis; Aspergillus; Aspergillus fumigatus; Attenuated; Biological Models; Blood; Blood Circulation; Blood Vessels; Breathing; Candidate Disease Gene; Cell Communication; Cell Line; Cells; Competence; Complement; Condition; Data; Depth; Development; Disease; Disruption; Distal; Endothelial Cells; Epithelial; Epithelial Cells; Filler; Foundations; Fright; Future; Gene Expression; Genes; Genetic; Germination; Growth; Hematogenous; Hyphae; Immune response; Immunocompromised Host; In Vitro; Incidence; Infection; Inflammatory; Invaded; Invasive; Investigation; Laboratories; Leukocyte-Adhesion Receptors; Leukocytes; Lung; Modeling; Morphogenesis; Mus; Numbers; Organ; Organism; Parents; Pathogenesis; Pathway interactions; Play; Predisposition; Production; Pulmonary alveolar structure; Rate; Regulation; Research Personnel; Role; Signal Transduction Pathway; Site; Specific qualifier value; Standards of Weights and Measures; Stress; Structure of parenchyma of lung; Surface; Testing; Tissues; Transcriptional Regulation; Vascular Endothelial Cell; Vascular Endothelium; Virulence; cell injury; cytokine; fungus; in vitro Model; mortality; mutant; novel strategies; novel therapeutics; programs; research study; therapeutic target; trait; transcription factor; Alveolus; Animals; Apoptosis; Aspergillosis; Aspergillus; Aspergillus fumigatus; Attenuated; Biological Models; Blood; Blood Circulation; Blood Vessels; Breathing; Candidate Disease Gene; Cell Communication; Cell Line; Cells; Competence; Complement; Condition; Data; Depth; Development; Disease; Disruption; Distal; Endothelial Cells; Epithelial; Epithelial Cells; Filler; Foundations; Fright; Future; Gene Expression; Genes; Genetic; Germination; Growth; Hematogenous; Hyphae; Immune response; Immunocompromised Host; In Vitro; Incidence; Infection; Inflammatory; Invaded; Invasive; Investigation; Laboratories; Leukocyte-Adhesion Receptors; Leukocytes; Lung; Modeling; Morphogenesis; Mus; Numbers; Organ; Organism; Parents; Pathogenesis; Pathway interactions; Play; Predisposition; Production; Pulmonary alveolar structure; Rate; Regulation; Research Personnel; Role; Signal Transduction Pathway; Site; Specific qualifier value; Standards of Weights and Measures; Stress; Structure of parenchyma of lung; Surface; Testing; Tissues; Transcriptional Regulation; Vascular Endothelial Cell; Vascular Endothelium; Virulence; cell injury; cytokine; fungus; in vitro Model; mortality; mutant; novel strategies; novel therapeutics; programs; research study; therapeutic target; trait; transcription factor

DESCRIPTION (provided by applicant): Invasive infections due to Aspergillus fumigatus are increasing, and despite new therapies are associated with greater than 50% mortality. During the pathogenesis of invasive aspergillosis, the organism interacts with several types of host cells, including pulmonary epithelial cells and endothelial cells. After being inhaled, A. fumigatus conidia adhere to and are internalized by the pulmonary epithelial cells that line the alveoli. In susceptible hosts, these conidia then germinate to form hyphae, which exit the pulmonary epithelial cells and invade the deeper tissues, most notably pulmonary blood vessels. Within these blood vessels, hyphae interact with vascular endothelial cells in two unique ways. First, hyphae from an infectious focus invade the abluminal surface of the blood vessel and then penetrate endothelial cells to gain access to the blood vessel lumen. Next, hyphal fragments are borne by the bloodstream to distal sites where they adhere to and penetrate the luminal surface of the endothelial cells and then invade the deep organs. To date, little is known about the genetic control of A. fumigatus virulence traits that influence the interactions of the organism with these host cells. In other pathogenic fungi, the conserved signal transduction pathways that control fungal morphogenesis and growth are also key regulators of virulence traits. Data from our group and others suggest that this paradigm holds true for A fumigatus. Thus, we hypothesize that the interactions of A fumigatus with pulmonary epithelial cells and the vascular endothelium are both developmental^ regulated and critical to the pathogenesis of invasive aspergillosis. Towards this end, we have identified a number of A fumigatus transcription factors predicted to govern fungal development. Mutants that are deficient in these candidate genes have been constructed. We have also developed animal and in vitro model systems to investigate the interaction of these mutants with epithelial and endothelial cells in a physiologically relevant manner. We hypothesize that these mutants will have abnormal development, aberrant interactions with host cells, and attenuated virulence. We will test this hypothesis by 1) determining the role of candidate transcription factors in the development and morpho- genesis of A fumigatus; 2) investigating the interactions of mutants deficient in candidate transcription factors with pulmonary epithelial cells and vascular endothelial cells in vitro; 3) characterizing the ability of a subset of these candidate transcription factors to modulate virulence and host response using murine models of invasive aspergillosis; and 4) identifying the downstream genes whose expression is regulated by candidate transcription factors that we find govern host cell interactions and virulence. These investigations will establish the roles of previously unexplored A. fumigatus transcription factors in governing development, host cell interactions, and virulence. They will also identify new genes that specify clearly defined, biologically relevant A fumigatus virulence traits. Collectively, these results will form the foundation for the future development of new therapeutic strategies for invasive aspergillosis.

描述（由申请人提供）：烟曲霉引起的侵入性感染正在增加，尽管新疗法与高于50％的死亡率有关。在侵入性曲霉病的发病机理中，该生物与几种类型的宿主细胞相互作用，包括肺上皮细胞和内皮细胞。吸入后，烟曲霉的分生孢子粘附在肺泡的肺上皮细胞上并内化。在易感宿主中，这些分生孢子然后发芽形成菌丝，从而退出肺部上皮细胞并侵入更深的组织，最著名的是肺血管。在这些血管中，菌丝以两种独特的方式与血管内皮细胞相互作用。首先，来自传染焦点的菌丝会侵入血管的排放表面，然后穿透内皮细胞以进入血管腔。接下来，菌丝碎片是由血液传到远端部位的，它们粘附并穿透了内皮细胞的腔表面，然后侵入深处器官。迄今为止，关于影响生物体与这些宿主细胞相互作用的毒素毒素性状的遗传控制知之甚少。在其他致病真菌中，控制真菌形态发生和生长的保守信号转导途径也是毒力性状的关键调节剂。来自我们小组和其他人的数据表明，这种范式对于富马图斯来说是正确的。因此，我们假设富瓜与肺上皮细胞和血管内皮的相互作用既受到侵入性曲霉病的发病机理的发育调节，又是至关重要的。为此，我们已经确定了许多预测的富瓜曲子转录因子，以控制真菌的发展。这些候选基因缺乏的突变体已构建。我们还开发了动物和体外模型系统，以生理相关的方式研究这些突变体与上皮细胞和内皮细胞的相互作用。我们假设这些突变体将具有异常发育，与宿主细胞的异常相互作用以及减弱的毒力。我们将通过1）确定候选转录因子在富米加图斯的发展和形成中的作用； 2）研究突变体在体外缺乏候选转录因子与肺部上皮细胞和血管内皮细胞的相互作用； 3）表征这些候选转录因子的子集使用浸润性曲霉病的鼠模型来调节毒力和宿主反应的能力； 4）识别下游基因，其表达受候选转录因子调节，我们发现宿主细胞相互作用和毒力。这些研究将确定先前未开发的烟曲霉转录因子在控制发育，宿主细胞相互作用和毒力中的作用。他们还将确定新的基因，这些基因指定明确定义的生物学相关的富玛曲和毒力性状。总的来说，这些结果将为侵入性曲霉病的新治疗策略的未来发展奠定基础。