Impact of Iron Supplementation on the Latency and Reactivation of Tuberculosis

补充铁对结核病潜伏期和再激活的影响

• 批准号: 8951858
• 负责人: Selvakumar Subbian
• 金额: $ 7.95万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951858
• 关键词: Achyrocline; Address; Affect; Anemia; Animal Model; Antibiotics; Area; Bacillus (bacterium); Bacteria; Biological Assay; Biological Models; Blood Circulation; Cell physiology; Cells; Cessation of life; Clinical Research; Control Animal; Country; Developing Countries; Disease; Disease Progression; Evolution; Excision; Exhibits; Future; Growth; Health; Health Policy; Homeostasis; Human; Immune; Immune system; Immunity; Immunocompetent; Immunosuppression; In Vitro; Individual; Infection; Infection Control; Infection prevention; Intake; Iron; Iron deficiency anemia; Laboratories; Lung; Measures; Metabolic; Metabolism; Micronutrients; Modeling; Morbidity - disease rate; Mycobacterium tuberculosis; Organ; Oryctolagus cuniculus; Pathogenesis; Patients; Phenotype; Physiological; Population; Public Health; Pulmonary Tuberculosis; Regimen; Reporting; Respiration; Role; Severity of illness; Source; Supplementation; Symptoms; Testing; Time; Tuberculosis; Virulence; Virulent; World Health Organization; base; combat; deprivation; design; disease transmission; immune function; improved; in vivo; insight; iron supplementation; mortality; nutrition; pathogen; programs; prophylactic; public health relevance; pulmonary granuloma; reactivation from latency; response

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is one of the world's most prevalent bacterial pathogen, infecting roughly one third of the human population and causing over 1 million deaths a year. More than 90% of healthy individuals infected by Mtb develop asymptomatic latent TB infection (LTBI) wherein the immune system drives the bacteria into a state of dormancy, from which they may emerge when immunity is compromised, establishing active disease. The ability of the immune system to control infection is greatly affected by nutrition, in particular by iron (Fe) intake and host Fe homeostasis. However, while adequate Fe intake is important for normal immune function, the relationship between host Fe status and Mtb infection is complicated by the fact that Fe is also necessary for Mtb growth and virulence. Indeed, several studies have shown that in anemic patients with LTBI Fe supplementation can trigger Mtb reactivation. Additionally, studies in the lab of our collaborator, Dr. Marcela Rodriguez, have shown that in vitro Fe deprivation drives Mtb cells into a state of dormancy, from which they emerge upon reintroduction of Fe to the medium. Together, these observations suggest that Fe supplementation to LTBI individuals may trigger reactivation of disease with renewed Mtb growth from a state of dormancy. This is a matter of concern because the World Health Organization has implemented a strategy of Fe supplementation to improve general health in developing countries with endemic TB. Therefore, it is essential to gain a comprehensive understanding of the effects of Fe status on host immunity during Mtb infection, with a particular emphasis on LTBI establishment and reactivation, ideally by using an animal model of Fe-supplementation during Mtb infection. We have developed a rabbit model that recapitulates key features of human Mtb infection, including maturation/evolution of lung granulomas, spontaneous establishment of LTBI and reactivation of LTBI upon immune suppression. In this application, we propose to use this rabbit model system to study the effects of Fe supplementation during LTBI. We propose two Specific Aims: in Aim 1 we will study the impact of host Fe supplementation on the early protective immunity against Mtb infection, while in Aim 2 we will investigate the effect of Fe supplementation on the establishment/reactivation of LTBI. In both Aims, the effects of a Fe supplementation regimen on Mtb infection will be assayed by a combination of bacteriological and immunological assays that are well established in our lab. Results obtained in these studies will reveal critical insights into the role of Fe homeostasis during Mtb infection, as well as guide future studies of the effects of micronutrients on the host immunity to infection and help design a better public health policy addressing Fe supplementation therapy to anemic patients in TB-endemic countries.

 描述（由申请人提供）：结核分枝杆菌（Mtb）是结核病（TB）的病原体，是世界上最流行的细菌病原体之一，感染约三分之一的人口，每年造成超过100万人死亡。超过90%的被Mtb感染的健康个体发展为无症状的潜伏性TB感染（LTBI），其中免疫系统驱使细菌进入休眠状态，当免疫力受损时，它们可以从休眠状态中出现，从而建立活动性疾病。免疫系统控制感染的能力受到营养的极大影响，特别是铁（Fe）的摄入和 宿主铁稳态。然而，虽然足够的铁摄入量是重要的正常免疫功能，宿主铁状态和结核分枝杆菌感染之间的关系是复杂的事实，铁也是必要的结核分枝杆菌的生长和毒力。事实上，几项研究表明，在患有LTBI的贫血患者中，Fe补充剂可触发Mtb再活化。此外，我们的合作者Marcela Rodriguez博士实验室的研究表明，体外Fe剥夺会使Mtb细胞进入休眠状态，在将Fe重新引入培养基后，它们就会出现。总之，这些观察结果表明，铁补充LTBI个人可能会触发重新激活的疾病与新的结核分枝杆菌生长从休眠状态。这是一个值得关注的问题，因为世界卫生组织已经实施了一项补充铁的战略，以改善结核病流行的发展中国家的总体健康状况。因此，它是必要的，以获得一个全面的了解铁状态对宿主免疫力在结核病感染，特别强调LTBI的建立和再激活，理想的是通过使用动物模型的铁补充结核病感染期间。我们已经开发了一种兔模型，其概括了人Mtb感染的关键特征，包括肺肉芽肿的成熟/演变、LTBI的自发建立和免疫抑制后LTBI的再激活。在这个应用中，我们建议使用这个兔子模型系统来研究在LTBI期间补充Fe的影响。我们提出两个具体目标：在目标1中，我们将研究宿主Fe补充对针对Mtb感染的早期保护性免疫的影响，而在目标2中，我们将研究Fe补充对LTBI的建立/再激活的影响。在这两个目标中，铁补充方案对结核分枝杆菌感染的影响将通过在我们实验室中充分建立的细菌学和免疫学测定的组合来测定。在这些研究中获得的结果将揭示关键的见解铁稳态的作用，结核病感染期间，以及指导未来的研究微量营养素对宿主免疫力的感染，并帮助设计一个更好的公共卫生政策解决铁补充治疗贫血患者在结核病流行的国家。