Type I Interferons in Immunity to Tuberculosis

I 型干扰素在结核病免疫中的作用

• 批准号: 7020706
• 负责人: Joel D. Ernst
• 金额: $ 41.26万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020706
• 关键词: Mycobacterium tuberculosis; antibacterial antibody; bacteria infection mechanism; bactericidal immunity; cytotoxic T lymphocyte; dendritic cells; drug resistance; genetically modified animals; helper T lymphocyte; immunogenetics; interferon alpha; interferon beta; interferon gamma; laboratory mouse; leukocyte activation /transformation; microarray technology; natural killer cells; nucleic acid chemical synthesis; pathologic process; polymerase chain reaction; suppressor T lymphocyte; tuberculosis; virulence; wild animals

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) causes more adult deaths worldwide than any other bacterium, and many strains are resistant to all first-line drugs. These properties contribute to the potential of Mtb as a major public health problem, as well as a potential agent of bioterrorism. In order to develop more effective means of prevention and control of tuberculosis, it is essential to better understand the mechanisms of protective immunity to Mtb. We have used a murine model to discover an essential role for type I interferons (IFNalphabeta) in control of virulent Mtb in vivo. We found that IFNlphabeta contributes to control of Mtb infection, revealed in mice that cannot respond to IFNalphabeta or to IFNgamma: STAT1-/- and IFNalphabetagammaR-/- mice exhibit a more rapid progression of infection and higher bacterial loads than IFNgammaR-/- mice. Moreover, we found that IFNalphabeta and IFNalphabeta-responsive genes are induced by infection with Mtb in vivo. We propose to test three (nonmutually exclusive) hypotheses of the roles of IFNalphabeta in control of Mtb. First, we will characterize the microbiologic and pathologic course of Mtb infection in mice that lack the ability to respond to IFNalphabeta, IFNgamma, or both, compared to wild-type mice. We will then test the hypothesis that IFNaa contributes to control of Mtb by regulating the same genes, or a subset of genes, regulated by IFNgamma, using microarray and real-time RT-PCR of RNA from lungs of specific mutant mice. Next, we will test the hypothesis that IFNaa regulates priming, differentiation, and trafficking ofCD4+and CD8+ T lymphocytes during Mtb infection. If this indicates that IFNaa promotes the development of the adaptive immune response to Mtb, we will determine whether IFNalphabeta acts indirectly by promoting the maturation and/or trafficking of dendritic cells. Finally, we will test the hypothesis that IFNalphabeta contributes to control of Mtb through natural killer (NK) cells, by characterizing the rate and extent of development, differentiation, and trafficking of NK cells in Mtb-infected mutant mice. If this implies that IFNalphabeta regulates NK cells during Mtb infection, we will determine whether Mtb infection of macrophages induces expression of ligands for stimulatory NK cell receptors. The proposed experiments will provide improved understanding of innate and adaptive immunity to Mtb, and may guide development of new means of prevention and treatment of tuberculosis, including drug-resistant tuberculosis.

描述（由申请人提供）：结核分枝杆菌（MTB）在全球范围内造成的成人死亡人数比任何其他细菌都要多，并且许多菌株对所有一线药物都有抗性。这些特性有助于MTB作为主要的公共卫生问题，以及生物恐怖主义的潜在推动者。为了开发更有效的预防和控制结核病的手段，必须更好地了解对MTB的保护性免疫的机制至关重要。我们已经使用鼠模型来发现I型干扰素（IFNALPHABETA）在体内控制毒力MTB中的重要作用。我们发现，IFNLPHABETA有助于控制MTB感染，这在无法反应IFNALPHABETA或IFNGAMMA的小鼠中：STAT1 - / - 和Ifnalphabetagagammar - / - 小鼠表现出比IFNGAMMAR-/ - / - / - / - - / - / - - / - - / - - / - / - - / - / - 鼠类的更快进展。此外，我们发现ifnalphabeta和ifnalphabeta响应基因是通过体内MTB感染诱导的。我们建议测试Ifnalphabeta控制MTB角色的三个（非物性排斥）假设。首先，与野生型小鼠相比，我们将表征小鼠中MTB感染的微生物和病理学病程，这些小鼠缺乏对Ifnalphabeta，Ifngamma或两者的反应能力。然后，我们将通过调节由Ifngamma调节的相同基因或一部分基因，使用微阵列和实时RT-PCR从特定突变小鼠的肺中调节RNNA，从而对MTB进行控制。接下来，我们将测试IFNAA在MTB感染过程中调节CD4+和CD8+ T淋巴细胞的启动，分化和运输的假设。如果这表明IFNAA促进了对MTB的自适应免疫反应的发展，我们将确定Ifnalphabeta是否通过促进树突状细胞的成熟和/或运输来间接起作用。最后，我们将通过表征MTB感染的突变体小鼠中NK细胞的发育速度和程度，通过自然杀伤（NK）细胞来促进MTB的速率和程度，从而测试IFNALPHABETA通过自然杀伤（NK）细胞对MTB的控制。如果这意味着IFNALPHABETA在MTB感染过程中调节NK细胞，我们将确定MTB的巨噬细胞感染是否会诱导配体的刺激性NK细胞受体的表达。拟议的实验将提高对MTB先天和适应性免疫的了解，并可能指导开发新的预防和治疗结核病的方法，包括耐药性结核病。