Novel TB Treatment Strategy - Optimization of Macrophage Responsiveness to IFNy

描述（由申请人提供）：结核分枝杆菌（Mtb）耐药形式引起的疾病的出现和传播代表了一个重大的全球威胁，迫切需要开发有效对抗耐药Mtb的预防和治疗策略。我们提出了一个新的概念，开发药物，低剂量的IFN-？并选择性地增加其对宿主抵抗感染的有益作用。IFN-？在实验小鼠模型和临床研究中，已经令人信服地证明了抗多种病原体（包括各种分枝杆菌物种）的抗结核途径。然而，病原体已经进化出不同的机制来抑制它。因此，治疗干预旨在恢复和维持IFN-？途径可能对慢性感染的管理产生重大和持久的影响。这种方法将是特别有用的治疗慢性感染的IFN-？这种途径起着重要的作用，但无论是全身性的（如在HIV和慢性TB感染中）还是局部性的（如在TB病变中）都受到损害。我们的工作将为开发一类靶向宿主而不是病原体的新型药物提供基础，因此对抗生素耐药细菌有效。通过帮助控制肺损伤，这些药物将减少耐药结核病的发展和传播。

DESCRIPTION (provided by applicant): The emergence and spread of disease caused by drug resistant forms of Mycobacterium tuberculosis (Mtb) represents a significant global threat, creating an urgent need for development of preventive and therapeutic strategies efficient against antibiotic-resistant Mtb. We propose a novel concept for developing drugs that cooperate with low doses of IFN-? and selectively increase its beneficial effect on host resistance to infections. Essentiality of the IFN-? 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 maintenance of the IFN-? 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.