Mycobacterial Dissemination and Persistence

分枝杆菌传播和持久性

• 批准号: 7936204
• 负责人: Jeffrey D. Cirillo
• 金额: $ 32.96万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936204
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Animal Model; Apoptosis; Bacillus (bacterium); Bacteria; Cavia; Cell model; Cells; Cessation of life; Dendritic Cells; Diagnosis; Disease; Drug resistance; Epithelial; Epithelial Cells; Epithelium; Event; Frequencies; Funding; Genes; Genus Mycobacterium; Granuloma; Growth; HIV Seropositivity; Hematogenous Spread; Human; Immune; Incidence; Individual; Infection; Inflammatory Response; Integration Host Factors; Lead; Lesion; Lung; Miliary Tuberculosis; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Necrosis; Organism; Pathogenesis; Patients; Permeability; Phagocytes; Play; Population; Prevention; Process; Public Health; Recruitment Activity; Regimen; Relapse; Research Design; Resistance; Role; Secondary Lesion; Severities; Severity of illness; Site; Spleen; Staging; Testing; Therapeutic; Tissues; Tuberculosis; Work; base; experience; improved; insight; latent infection; macrophage; mortality; mycobacterial; novel; pathogen; prevent; public health relevance; therapeutic vaccine; tissue culture; treatment strategy; vaccination against tuberculosis

DESCRIPTION (provided by applicant): The high incidence of tuberculosis worldwide is due to a number of factors, including the high frequency of co-infection in AIDS patients, continued emergence of drug resistance, incomplete sterilizing activity of therapeutic regimen and the ability of M. tuberculosis (Mtb) to persist in the host indefinitely. The increasing incidence of extrapulmonary tuberculosis is a grave public health concern because of its higher mortality rates and the need for extended therapy. High HIV-tuberculosis co-infection rates are a likely cause of the increasing incidence of extrapulmonary tuberculosis, since dissemination occurs in >50% of AIDS patients, but only 5-20% in HIV-negative individuals. Miliary tuberculosis, a severe form of tuberculosis occurring in approximately 8% of the extrapulmonary cases, has a much higher rate of mortality. These observations suggest that dissemination is a key factor in the severity of tuberculosis. Since lesions that lead to reactivation are secondary lesions, dissemination also plays an important role in establishment of latent infections, which affect nearly one-third of the world's population. Despite the importance of dissemination in the severity of disease and establishment of latency, the molecular mechanisms involved are poorly understood. In order to better understand how tuberculosis disseminates and whether these mechanisms result in greater disease severity and/or contribute to latency, we plan to identify and characterize the mycobacterial factors involved in both processes. There are four alternative hypotheses regarding how dissemination might occur in tuberculosis: 1) transit through the epithelium within migrating macrophages/dendritic cells, 2) direct invasion of the epithelium, 3) cytopathic and inflammatory response in epithelium leading to permeability, and 4) encroachment of granulomas into vessels allowing release of bacteria/infected cells. Currently, only a single Mtb gene, hbhA, has been identified that affects dissemination. Our own work and that of others indicate mycobacteria have numerous genes that affect the efficiency of macrophage and epithelial cell infection. It has also been shown that growth of Mtb and other mycobacterial species within epithelial cells and phagocytic cells enhances their ability to infect macrophages. The presence of numerous regulated and constitutive mechanisms of host cell infection suggest there is a spectrum of mycobacterial genes involved in tissue invasion and dissemination that remain to be identified. Our specific aims are to: 1) identify the Mtb genes involved in hematogenous spread from the lung, 2) detailed comparison of dissemination in mice and guinea pigs, and 3) dissect the molecular mechanisms by which the mel2 locus affects dissemination and persistence. We will take advantage of our interdisciplinary team's experience in mycobacterial molecular genetics, tissue culture models and animal models to provide insight into the molecular basis of dissemination and persistence, which are critical stages of tuberculosis pathogenesis. PUBLIC HEALTH RELEVANCE: Tuberculosis remains one of the most important causes of morbidity and mortality in humans worldwide, infecting nearly one-third of the world's population and causing more than two million deaths each year. Latent infections are responsible for the majority of those individuals infected and mortality is higher in extrapulmonary infections that arise from dissemination of the bacteria to other tissues. The current proposal is focused on understanding how dissemination occurs and its relationship to latency so that we can better treat, prevent and diagnose tuberculosis.

描述（由申请人提供）：全球结核病的高发病率是由于许多因素造成的，包括艾滋病患者合并感染的高频率、耐药性的持续出现、治疗方案的不完全灭菌活性以及M.结核病（Mtb）在宿主体内无限期存在。肺外结核的发病率日益增加，是一个严重的公共卫生问题，因为其死亡率较高，需要延长治疗。艾滋病毒-结核病合并感染率高可能是肺外结核发病率增加的一个原因，因为>50%的艾滋病患者发生播散，但在艾滋病毒阴性个体中仅为5-20%。粟粒性结核是一种严重的结核病，约占肺外病例的8%，死亡率高得多。这些观察结果表明，传播是结核病严重程度的一个关键因素。由于导致再激活的病变是继发性病变，因此传播在潜伏感染的建立中也起着重要作用，这影响了世界上近三分之一的人口。尽管传播在疾病的严重程度和潜伏期的建立中的重要性，但所涉及的分子机制知之甚少。为了更好地了解结核病是如何传播的，以及这些机制是否会导致更严重的疾病和/或导致潜伏期，我们计划识别和表征这两个过程中涉及的分枝杆菌因素。关于结核病如何发生传播，有四种替代假设：1）通过迁移巨噬细胞/树突细胞内的上皮转运，2）直接侵入上皮，3）上皮中的细胞病变和炎症反应导致渗透性，以及4）肉芽肿侵入血管，允许细菌/感染细胞释放。目前，只有一个单一的结核分枝杆菌基因，hbhA，已被确定影响传播。我们自己和其他人的工作表明分枝杆菌有许多影响巨噬细胞和上皮细胞感染效率的基因。还显示Mtb和其他分枝杆菌物种在上皮细胞和吞噬细胞内的生长增强了它们感染巨噬细胞的能力。宿主细胞感染的许多调节和组成性机制的存在表明存在一系列参与组织侵袭和传播的分枝杆菌基因，这些基因仍有待鉴定。我们的具体目标是：1）鉴定涉及从肺的血行播散的Mtb基因，2）详细比较小鼠和豚鼠中的播散，和3）剖析mel 2基因座影响播散和持久性的分子机制。我们将利用我们跨学科团队在分枝杆菌分子遗传学、组织培养模型和动物模型方面的经验，深入了解结核病发病机制的关键阶段--传播和持久性的分子基础。公共卫生相关性：结核病仍然是全世界人类发病和死亡的最重要原因之一，感染了世界近三分之一的人口，每年造成200多万人死亡。潜伏性感染是大多数受感染个体的原因，并且由细菌传播到其他组织引起的肺外感染的死亡率较高。目前的建议侧重于了解传播如何发生及其与潜伏期的关系，以便我们能够更好地治疗，预防和诊断结核病。

项目成果

The Mycobacterium marinum mel2 locus displays similarity to bacterial bioluminescence systems and plays a role in defense against reactive oxygen and nitrogen species.

• DOI: 10.1186/1471-2180-7-4
• 发表时间: 2007-01-19
• 期刊: BMC microbiology
• 影响因子: 4.2
• 作者: Subbian S;Mehta PK;Cirillo SL;Cirillo JD
• 通讯作者: Cirillo JD

Fiber optic microendoscopy for preclinical study of bacterial infection dynamics.

• DOI: 10.1364/boe.2.001121
• 发表时间: 2011-04-07
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Mufti N;Kong Y;Cirillo JD;Maitland KC
• 通讯作者: Maitland KC

Identification of Mycobacterium marinum macrophage infection mutants.

海分枝杆菌巨噬细胞感染突变体的鉴定。

• DOI: 10.1016/j.micpath.2005.12.002
• 发表时间: 2006
• 期刊: Microbial pathogenesis
• 影响因子: 3.8
• 作者: Mehta,ParmodK;Pandey,AmitK;Subbian,Selvakumar;El-Etr,SaharH;Cirillo,SuatLG;Samrakandi,MustaphaM;Cirillo,JeffreyD
• 通讯作者: Cirillo,JeffreyD

Random inducible controlled expression (RICE) for identification of mycobacterial virulence genes.

• DOI: 10.1016/j.tube.2011.10.013
• 发表时间: 2011-12
• 期刊: Tuberculosis (Edinburgh, Scotland)
• 作者: Janagama HK;Hassounah HA;Cirillo SL;Cirillo JD
• 通讯作者: Cirillo JD

Bioluminescent imaging of Borrelia burgdorferi in vivo demonstrates that the fibronectin-binding protein BBK32 is required for optimal infectivity.

体内伯氏毛毛毛毛毛虫的生物发光成像表明，纤连蛋白结合蛋白BBK32是最佳感染性所必需的。

• DOI: 10.1111/j.1365-2958.2011.07801.x
• 发表时间: 2011-10
• 期刊: Molecular microbiology
• 影响因子: 3.6
• 作者: Hyde JA;Weening EH;Chang M;Trzeciakowski JP;Höök M;Cirillo JD;Skare JT
• 通讯作者: Skare JT