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（M.tb）是一个重大的全球威胁，迫切需要开发预防和 有效对抗抗结核杆菌的治疗策略我们提出了一个新的概念， 与低剂量IFNg合作并选择性地增加其对宿主的有益作用的药物 抵抗感染。IFNγ途径对多种病原体的抗性相似， 包括各种分枝杆菌物种，已经令人信服地证明， 模型和临床研究。然而，病原体已经进化出多种机制来抑制它。因此， 旨在恢复和维持IFNγ通路的治疗干预可能会产生显著的 对慢性感染的管理具有长期持久的影响。这种方法将特别有用， 治疗IFN β途径发挥重要作用但受损的慢性感染， 全身性（如HIV和慢性TB感染）或局部性（如TB病灶内）。我们的工作将提供一个 为开发一类靶向宿主而非病原体的新型药物奠定了基础，因此有效 对抗抗生素耐药菌。通过帮助控制肺损伤，这些药物将减少 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.