Rickettsia-host interface and multiple paths to invasion

立克次体-宿主界面和多种入侵途径

• 批准号: 10626741
• 负责人: Mohammed Sayeedur Rahman
• 金额: $ 66.25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626741
• 关键词: Address; Africa; Anti-Inflammatory Agents; Antibodies; Arizona; Arthropods; Autophagocytosis; Autophagosome; Bacteria; Bite; Blood; Bone Marrow; Boutonneuse Fever; California; Cd68; Cells; Central America; Complex; Cytokine Signaling; Cytosol; Data; Development; Disease Outbreaks; Distant; Endemic Flea-Borne Typhus; Endothelial Cells; Environment; Epidemic; Etiology; Europe; Goals; Growth; Host Defense; Human; Immune; Infection; Inflammasome; Inflammatory; Inflammatory Response Pathway; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-10; Invaded; Knowledge; Life Cycle Stages; Life Style; Link; Macrophage; Middle East; Organ; PIK3CG gene; Pathogenicity; Pathway interactions; Play; Proteins; Publishing; Reporting; Research; Rickettsia; Rickettsia Infections; Rickettsia conorii; Rickettsia prowazekii; Rickettsia rickettsii; Rickettsia typhi; Risk; Rocky Mountain Spotted Fever; Role; Signal Transduction; Site; Skin; South America; Spleen; Stream; Structure; Systemic disease; TNF gene; Testing; Texas; Time; Tissues; Transforming Growth Factor beta; Typhus; Ubiquitination; United States; Up-Regulation; Vaccines; Virulence; Virulent; Wild Type Mouse; arthropod-borne; cytokine; draining lymph node; effective intervention; flea-borne; host colonization; human pathogen; inhibition of autophagy; member; microbial; microbicide; monocyte; pathogen; pathogenic bacteria; prevent; programs; recruit; response; spotted fever; therapeutically effective; tick-borne; trafficking

PROJECT SUMMARY Species in the genus Rickettsia are Gram-negative obligate intracellular bacteria with both symbiotic and pathogenic lifecycles. The global impact of rickettsial infections is illustrated by the resurgence of infections of humans with R. rickettsia (etiologic agent of Rocky Mountain Spotted Fever) in South and Central America, or R. conorii (Boutonneuse fever) in Europe, the Middle East, and Africa. Strikingly, tick- and flea-borne rickettsial diseases are also on the rise in the United States, as exemplified by recent outbreaks of R. rickettsii in Arizona and R. typhi (etiologic agent of murine typhus) in California and Texas, further highlighting the threats of rickettsial diseases. There are currently no vaccines to prevent rickettsioses and our insufficient understanding of rickettsial intracellular lifestyle hinders the progression towards the development of effective therapeutics against these increasingly recognized bacterial pathogens. Over the past four years, we identified a complex mechanism by which pathogenic rickettsiae utilize secreted effectors to facilitate colonization by manipulating ER structures or by modulating intracellular trafficking to subvert host defense pathways. However, the precise mechanisms by which virulent Rickettsia species utilize this effector arsenal to subvert host innate defense pathways to support intracellular lifestyle in endothelial cells or macrophages (MΦ) remains ill-defined. To address these knowledge gaps, this renewal application proposes to: i) decipher how virulent Rickettsia species utilize their effector repertoire to manipulate autophagic responses to colonize host cells, and ii) determine the mechanism(s) by which effectors of virulent, but not avirulent, Rickettsia species suppress inflammasome activation and manipulate MΦ polarization to promote host dissemination. Our overall goal is to test the hypothesis that effectors from virulent species of Rickettsia, like Risk1, induce autophagy to negatively regulate inflammasome activation and skews MΦ polarization from a M1 to M2 bias to facilitate host colonization. To test our hypothesis, in Aim 1, we will define the mechanism(s) by which pathogenic Rickettsia subvert autophagosomal maturation to promote host colonization. In Aim 2, we will decipher the mechanism(s) underlying subversion of inflammasome responses and manipulation of MΦ polarization by pathogenic Rickettsia species. These Aims are intended to unveil a link by which effectors of pathogenic Rickettsia species manipulate autophagy to subvert inflammasome-dependent proinflammatory cytokine signaling and skew MΦ polarization from a microbicidal milieu (M1-MΦ) to a more favorable pro- microbial environment (M2-MΦ). These studies will lead to the identification of a link that could be exploited for anti-virulence strategy.

项目概要 立克次体属中的物种是革兰氏阴性专性细胞内细菌，具有共生和 感染的死灰复燃说明了立克次体感染的全球影响。 南美洲和中美洲感染立克次氏体（落基山斑疹热的病原体）的人群， 或欧洲、中东和非洲的 R. conorii（布通诺热），引人注目的是，由蜱和跳蚤传播。 立克次体疾病在美国也呈上升趋势，最近爆发的立克次体病就是一个例子 亚利桑那州和加利福尼亚州和德克萨斯州的伤寒杆菌（鼠伤寒病原体），进一步强调了 立克次体疾病的威胁 目前没有疫苗可以预防立克次体病，而且我们的疫苗也不足。 对立克次体细胞内生活方式的了解阻碍了有效性发展的进展 在过去的四年里，我们发现了针对这些日益被认可的细菌病原体的疗法。 致病性立克次体利用分泌的效应子促进定植的复杂机制 操纵内质网结构或通过调节细胞内运输来破坏宿主防御途径。 然而，剧毒立克次体物种利用这种效应子库来破坏的精确机制 宿主先天防御途径支持内皮细胞或巨噬细胞的细胞内生活方式 (MΦ) 为了解决这些知识差距，本更新申请建议：i) 解释如何解决。 剧毒立克次体利用其效应子库来操纵自噬反应以定植宿主 细胞，以及 ii) 确定有毒力而非无毒力立克次体物种效应子的机制 抑制炎性体激活并操纵 MΦ 极化以促进宿主传播。 总体目标是检验以下假设：来自立克次体强毒物种的效应器（如 Risk1）会诱导 自噬负向调节炎症小体激活并使 MΦ 极化从 M1 偏向 M2 为了促进宿主定植，为了检验我们的假设，在目标 1 中，我们将定义其机制。 致病性立克次体破坏自噬体成熟以促进宿主定植 在目标 2 中，我们将 破译炎症体反应颠覆和 MΦ 操纵的潜在机制 这些目的旨在揭示致病性立克次体物种的效应器之间的联系。 致病性立克次体操纵自噬破坏炎症小体依赖性促炎症 细胞因子信号传导和偏斜 MΦ 极化从杀菌环境 (M1-MΦ) 到更有利的亲 这些研究将确定可利用的链接。 用于抗病毒策略。

项目成果

Rickettsia-host interaction: strategies of intracytosolic host colonization.

立克次体-宿主相互作用：胞质内宿主定植的策略。

• 发表时间: 2021-04-05
• 作者: Voss, Oliver H;Rahman, M Sayeedur
• 通讯作者: Rahman, M Sayeedur

Pathogenic, but Not Nonpathogenic, Rickettsia spp. Evade Inflammasome-Dependent IL-1 Responses To Establish an Intracytosolic Replication Niche.

致病性，但不是非致病性，立克次体属。

• 发表时间: 2021-02-22
• 影响因子: 6.4
• 作者: Voss, Oliver H;Cobb, Jennifer;Gaytan, Hodalis;Rivera Díaz, Natalia;Sanchez, Rigoberto;DeTolla, Louis;Rahman, M Sayeedur;Azad, Abdu F
• 通讯作者: Azad, Abdu F

The Rickettsial Ankyrin Repeat Protein 2 Is a Type IV Secreted Effector That Associates with the Endoplasmic Reticulum.

立克次体锚蛋白重复蛋白 2 是一种与内质网相关的 IV 型分泌效应蛋白。

• 发表时间: 2018
• 影响因子: 6.4
• 作者: Lehman, Stephanie S;Noriea, Nicholas F;Aistleitner, Karin;Clark, Tina R;Dooley, Cheryl A;Nair, Vinod;Kaur, Simran Jeet;Rahman, M Sayeedur;Gillespie, Joseph J;Azad, Abdu F;Hackstadt, Ted
• 通讯作者: Hackstadt, Ted

Conjugative Transposons and Their Cargo Genes Vary across Natural Populations of Rickettsia buchneri Infecting the Tick Ixodes scapularis.

接合转座子及其货物基因在感染肩胛硬蜱的布氏立克次体自然种群中存在差异。

• 发表时间: 2018
• 作者: Hagen, Rachael;Verhoeve, Victoria I;Gillespie, Joseph J;Driscoll, Timothy P
• 通讯作者: Driscoll, Timothy P

Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes Rickettsia typhi Intracellular Survival.

Risk1 是一种磷脂酰肌醇 3 激酶效应器，可促进伤寒立克次体细胞内存活。

• 发表时间: 2020
• 影响因子: 6.4
• 作者: Voss, Oliver H;Gillespie, Joseph J;Lehman, Stephanie S;Rennoll, Sherri A;Beier;Rahman, M Sayeedur;Azad, Abdu F
• 通讯作者: Azad, Abdu F