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，每年导致超过 100 万人死亡。超过 90% 的感染 Mtb 的健康个体会出现无症状潜伏性 TB 感染 (LTBI)，免疫系统会驱使细菌进入休眠状态，当免疫力受到损害时，它们可能会出现，从而形成活动性疾病。免疫系统控制感染的能力很大程度上受到营养的影响，特别是铁 (Fe) 摄入量和免疫系统控制感染的能力。 然而，虽然充足的铁摄入对于正常的免疫功能很重要，但宿主铁的状态和结核分枝杆菌感染之间的关系却很复杂，因为铁对于结核分枝杆菌的生长和毒力来说也是必需的。补充 LTBI Fe 的贫血患者可以触发 Mtb 重新激活，我们的合作者 Marcela Rodriguez 博士的实验室研究表明，体外缺铁会导致 Mtb 细胞进入休眠状态。总之，这些观察结果表明，对 LTBI 个体补充铁可能会导致疾病重新激活，结核分枝杆菌从休眠状态重新生长，这是一个值得关注的问题，因为世界卫生组织已经实施了这一措施。补充铁以改善患有地方性结核病的发展中国家的总体健康状况因此，有必要全面了解结核分枝杆菌感染期间铁状态对宿主免疫的影响，特别是 LTBI 的建立和重新激活。理想情况下，我们开发了一种兔模型，该模型概括了人类 Mtb 感染的关键特征，包括肺肉芽肿的成熟/演变、LTBI 的自发形成以及免疫抑制后 LTBI 的重新激活。在本申请中，我们建议使用该兔子模型系统来研究 LTBI 期间补充铁的影响，我们提出两个具体目标：在目标 1 中，我们将研究补充铁对宿主的影响。针对 Mtb 感染的早期保护性免疫，而在目标 2 中，我们将研究补充铁对 LTBI 建立/重新激活的影响。在这两个目标中，将通过细菌学组合来分析铁补充方案对结核分枝杆菌感染的影响。这些研究中获得的结果将揭示对结核分枝杆菌感染期间铁稳态作用的重要见解，并指导未来微量营养素影响的研究。评估宿主对感染的免疫力，并帮助设计更好的公共卫生政策，为结核病流行国家的贫血患者提供铁补充剂治疗。