Novel TB Treatment Strategy - Optimization of Macrophage Responsiveness to IFNy

摘要 耐药结核分枝杆菌引起的疾病的出现和传播 (结核分枝杆菌)是一个重大的全球威胁，迫切需要制定预防性和可持续发展战略 对耐药结核分枝杆菌有效的治疗策略。我们提出了一种新的概念来开发 与低剂量干扰素协同作用并选择性增加其对宿主有益作用的药物 对感染的抵抗力干扰素γ途径在抵抗多种病原体中的重要性 包括各种分枝杆菌，已经在实验小鼠身上令人信服地证明了 模型和临床研究。然而，病原体已经进化出不同的机制来抑制它。因此， 旨在恢复和维持干扰素γ途径的治疗干预可能会产生显著的 以及对慢性感染管理的长期影响。此方法将在以下方面特别有用 干扰素途径发挥重要作用但受到损害的慢性感染的治疗， 无论是系统性的(如艾滋病毒和慢性结核病感染)还是局部的(如结核病损内)。我们的工作将提供一个 为开发针对宿主而不是病原体的新型药物奠定了基础，因此是有效的 对抗抗药性细菌。通过帮助控制肺损伤，这些药物将减缓病情的发展 以及耐药结核病的传播。

Abstract The emergence and spread of disease caused by drug resistant forms of Mycobacterium tuberculosis (M.tb) represents a significant global threat, creating an urgent need for development of preventive and therapeutic strategies efficient against antibiotic-resistant M.tb. We propose a novel concept for developing drugs that cooperate with low doses of IFNg and selectively increase its beneficial effect on host resistance to infections. Essentiallity of the IFNγ pathway in resistance to a broad range of pathogens, including various mycobacterial species, has been convincingly demonstrated both in experimental mouse models and clinical studies. However, pathogens have evolved diverse mechanisms to suppress it. Therefore, therapeutic interventions aimed at restoration and maintanence of the IFNγ pathway may produce significant and long lasting impact on management of chronic infections. This approach will be especially useful in treatment of those chronic infections where the IFN pathway plays an essential role, but is compromised, either systemically (as in HIV and chronic TB infection) or locally (as within TB lesions). Our work will provide a basis for the development of a novel class of drugs targeting the host, not the pathogen, and therefore effective against antibiotic resistant bacteria. By helping control lung damage, these drugs will reduce the development and spread of drug resistant forms of tuberculosis.