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: 10157426
• 负责人: Lidiya Dubytska
• 金额: $ 10.25万
• 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/10157426
• 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; Immune response; Immune system; Immunity; Immunoblotting; Individual; Infection; Innate Immune Response; Interleukin-1 beta; Interleukin-18; Investigation; Lactate Dehydrogenase; Legionella; Legionella pneumophila; Legionnaires' Disease; Literature; 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; Work; atypical pneumonia; base; combat; cytokine; cytotoxicity; design; disorder control; gene function; immunoregulation; improved; interleukin-1beta-converting enzyme inhibitor; macrophage; microbial; mutant; pathogen; pathogenic bacteria; pro-apoptotic protein; programs; response; restoration; trafficking; transcriptome; transcriptome sequencing

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.

抽象的。军团属的属有60多种，其中20种与军团义务员有关 疾病，一种非典型肺炎的形式。超过90％的军团病病例是由L引起的。 肺炎血清群1。军团倾向于在铅皮系统生物膜和变形虫囊肿上定居 抗水净化处理。军团菌的能力。坚持并在变形虫中繁殖 人类并引起临床疾病取决于一组病毒基因和基因的坐标调节 与先天和获得的宿主防御效果作斗争的功能。因此，这是主要目标 提案是阐明肺炎军团菌已经演变为克服宿主的分子机制 先天免疫反应并允许其建立感染。 肺炎乳杆菌基因组包含编码两种类型IV（TIVS）分泌的基因簇 系统； LVH和DOT/ICM。虽然DOT/ICM的遗传组织及其在病毒中的作用已得到很好的确立，但 关于LVH TIVSS的作用的信息有限。缺乏LVH TIVS的军团菌菌株具有 细胞毒性明显降低。此外，LVH TIVSS在L.宿主细胞感染中起着重要作用。 肺炎在30°C生长，并在吞噬体酸化的有效延迟下生长。肺炎乳杆菌LVH基因座 孵育后，需要恢复点/ICM突变体中的入口和细胞内乘法所必需 在水和变形虫的环境中。我们已经证明了肺炎军团的LVH TIVSS机械 位于细胞杆上，据报道这种定位对于其他病原体中的病毒很重要。 我们还证明，LVH TIVSS对于Legionella菌株时的宿主caspase-3/7激活很重要 在30°C以下生长。根据我们的初步数据和文献数据，我们的中心假设是 LVH从环境感染下有助于军团菌病毒，并调节细胞的晚期 感染并进一步传播细菌。我们将检验我们的中心假设，并通过 评估LVH TIVSS在宿主细胞免疫，基因表达和 程序性细胞死亡。 揭示LVH功能将发现可能被利用的细菌病原体潜在弱点的位点 为了进行热干预，开发有理，最佳有效疫苗和疾病控制。那， 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病毒 感染过程中的因素，产生受保护的反应，以及LEVINELLE 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肺炎乳杆菌改变的途径或网络的重要信息 宿主中的TIVSS可能为开发新的有针对性治疗的基础奠定了基础。