Role of Legionella pneumophila Lvh TIVSS in virulence

嗜肺军团菌 Lvh TIVSS 在毒力中的作用

• 批准号: 10624955
• 负责人: Lidiya Dubytska
• 金额: $ 10.5万
• 依托单位: SOUTHERN UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624955
• 关键词: ANXA5 gene; Affect; Amoeba genus; Anaplasma phagocytophilum; Antibodies; Apoptosis; Apoptotic; Bacteria; Biological Assay; CASP3 gene; CASP7 gene; CASP8 gene; Caspase; Cell Death; Cells; Clinical; Cyst; Data; Development; Disease; Environment; Future; Gene Cluster; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Goals; Health; Host Defense; Human; IL18 gene; Immune response; Immune system; Immunity; Incubated; Individual; Infection; Innate Immune Response; Interleukin-1 beta; Investigation; Lactate Dehydrogenase; Legionella; Legionella pneumophila; Legionnaires' Disease; Literature; Macrophage; Measures; Membrane; Messenger RNA; Microbial Biofilms; Mitochondria; Molecular; Organelles; Outcome; Pathogenesis; Pathway interactions; Phagosomes; Play; Plumbing; Pneumonia; Process; Promega; Proteins; Proteome; Reporting; Resistance; Role; Signal Transduction; Site; System; Testing; Therapeutic; Therapeutic Intervention; Time; Type IV Secretion System Pathway; United States; Vaccines; Virulence; Virulence Factors; Virulent; Water; Water Purification; Western Blotting; Work; atypical pneumonia; combat; cytokine; cytotoxicity; design; disorder control; gene function; immunoregulation; improved; interleukin-1beta-converting enzyme inhibitor; microbial; mutant; pathogen; pathogenic bacteria; pro-apoptotic protein; programs; response; restoration; trafficking; transcriptome; transcriptome sequencing; virulence gene

Abstract. The Legionella genus has more than 60 species from which 20 are associated with Legionnaires’ disease, a form of atypical pneumonia. More than 90% of Legionnaires’ disease cases are caused by L. pneumophila serogroup 1. Legionella tends to colonize plumbing system biofilms and amoebae cysts which are resistant to water purification treatment. The ability of Legionella spp. to persist and multiply in amoeba and humans and cause clinical disease depends on a set of virulence genes and on the coordinate regulation of gene functions that combat the effects of innate and acquired host defenses. Therefore, the main objective of this proposal is to elucidate the molecular mechanisms that Legionella pneumophila has evolved to overcome host innate immune responses and allow it to establish an infection. The L. pneumophila genome contains clusters of genes that encode two types of type IV (TIVSS) secretion systems; lvh and dot/icm. While the genetic organization of dot/icm, and its role in virulence is well established, there is limited information about the role of Lvh TIVSS. The Legionella strains that lack Lvh TIVSS have markedly reduced cytotoxicity. Additionally, Lvh TIVSS plays an important role in host-cell infection by L. pneumophila grown at 30°C, and in the effective delay of phagosome acidification. The L. pneumophila lvh locus is required for the restoration of entry and intracellular multiplication in dot/icm mutants following incubation in water and amoeba encystment. We have demonstrated that Legionella pneumophila’s Lvh TIVSS machinery localize at cell poles, and such localization has been reported to be important for virulence in other pathogens. We also demonstrated that Lvh TIVSS is important for host-cell caspase-3/7 activation when Legionella strains are grown under 30°C. Based on our preliminary data and data from the literature, our central hypothesis is that Lvh contributes to Legionella virulence under infection from the environment and regulates late stages of cellular infection and further dissemination of bacteria. We will test our central hypothesis and attain our objective by evaluating the role of Lvh TIVSS in the modulation of host cell immunity, gene expression, and programmed cell death. Revealing Lvh functions will uncover sites of potential weakness in bacterial pathogens that may be exploited for therapeutic intervention, development of rational, optimally efficacious vaccines, and disease control. Thus, the main goal of this project is to understand how the host-cell immune system recognizes microbial virulence factors during infection, produces a protective response, and the mechanism by which Legionella Lvh can inhibit this protective response. The results from this work will have an important positive impact on human health because they will provide important information about pathways or networks altered by L. pneumophila Lvh TIVSS in the host, which may lay the groundwork for the development of a new class of targeted treatments.

抽象。军团菌属有60多个种，其中20个与军团菌相关。 一种非典型肺炎。90%以上的军团病病例是由军团菌引起的。 嗜肺菌血清群1。军团菌倾向于定植于管道系统生物膜和阿米巴包囊， 耐水净化处理。军团菌属的能力。在变形虫中存活和繁殖， 人类致病和引起临床疾病依赖于一组毒力基因和基因的协调调控 抵抗先天和后天宿主防御的功能。因此，本报告的主要目的 一项提案是阐明嗜肺军团菌进化以克服宿主的分子机制， 先天免疫反应，并允许它建立感染。 洛杉矶嗜肺菌基因组包含编码两种IV型（TIVSS）分泌物的基因簇 系统; LVH和DOT/ICM。虽然dot/icm的遗传结构及其在毒力中的作用已经很好地建立， 关于Lvh TIVSS的作用的信息有限。缺乏Lvh TIVSS的军团菌菌株 细胞毒性明显降低。此外，Lvh TIVSS在L. pneumophila生长在30°C，并在吞噬体酸化的有效延迟。洛杉矶嗜肺菌LVH基因座 对于孵育后dot/icm突变体的进入和细胞内增殖的恢复是必需的 水和阿米巴包囊中。我们已经证明嗜肺军团菌的Lvh TIVSS机制 定位于细胞两极，并且据报道这种定位对于其他病原体中的毒力是重要的。 我们还证明，当军团菌菌株感染宿主细胞时，Lvh TIVSS对宿主细胞caspase-3/7的活化是重要的。 在30°C下生长。根据我们的初步数据和文献数据，我们的中心假设是， Lvh有助于军团菌在环境感染下的毒力，并调节细胞增殖的晚期阶段。 感染和细菌进一步传播。我们将检验我们的中心假设，并达到我们的目标， 评价Lvh TIVSS在调节宿主细胞免疫、基因表达和 程序性细胞死亡 揭示Lvh功能将揭示可能被利用的细菌病原体的潜在弱点 用于治疗性干预、开发合理的、最有效的疫苗和疾病控制。因此，在本发明中， 该项目的主要目标是了解宿主细胞免疫系统如何识别微生物毒力 在感染过程中的因素，产生保护性反应，和军团菌Lvh可以抑制的机制， 这种保护性反应。这项工作的结果将对人类健康产生重要的积极影响 因为它们将提供有关L改变的途径或网络的重要信息。嗜肺菌 宿主中的TIVSS，这可能为开发一类新的靶向治疗奠定基础。