Hawn Thomas R, Shah Javeed A, Kalman Daniel
Department of Medicine, University of Washington, Seattle, WA, USA.
Immunol Rev. 2015 Mar;264(1):344-62. doi: 10.1111/imr.12255.
Despite the availability of Mycobacterium tuberculosis (Mtb) drugs for over 50 years, tuberculosis (TB) remains at pandemic levels. New drugs are urgently needed for resistant strains, shortening duration of treatment, and targeting different stages of the disease, especially for treatment during human immunodeficiency virus co-infection. One solution to the conundrum that antibiotics kill the bacillus yet select for resistance is to target the host rather than the pathogen. Here, we discuss recent progress in so-called 'host-directed therapeutics' (HDTs), focusing on two general mechanistic strategies: (i) HDTs that disrupt Mtb pathogenesis in macrophages and (ii) immunomodulatory HDTs that facilitate protective immune responses that kill Mtb or reduce deleterious responses that exacerbate disease. HDTs hold significant promise as adjunctive therapies in that they are less likely to engender resistance, will likely have efficacy against antibiotic-resistant strains, and may have activity against non-replicating Mtb. However, TB is a complex and variegated disease, and human populations exhibit significant diversity in their immune responses to it, which presents a complicated landscape for HDTs to navigate. Nevertheless, we suggest that a detailed mechanistic understanding of drug action, together with careful selection of disease stage targets and dosing strategies may overcome such limitations and allow the development of HDTs as effective adjunctive treatment options for TB.
尽管已有用于治疗结核分枝杆菌（Mtb）的药物50多年，但结核病（TB）仍处于大流行水平。对于耐药菌株、缩短治疗疗程以及针对疾病的不同阶段，尤其是在人类免疫缺陷病毒合并感染期间的治疗，迫切需要新型药物。抗生素能杀死结核杆菌但会导致耐药这一难题的一个解决方案是针对宿主而非病原体。在此，我们讨论所谓“宿主导向疗法”（HDTs）的最新进展，重点关注两种一般的作用机制策略：（i）破坏巨噬细胞中结核分枝杆菌致病机制的HDTs，以及（ii）促进保护性免疫反应以杀死结核分枝杆菌或减少加剧疾病的有害反应的免疫调节性HDTs。HDTs作为辅助疗法具有巨大潜力，因为它们产生耐药性的可能性较小，可能对抗生素耐药菌株有效，并且可能对非复制型结核分枝杆菌有活性。然而，结核病是一种复杂多样的疾病，人群对其免疫反应存在显著差异，这给HDTs的应用带来了复杂局面。尽管如此，我们认为对药物作用的详细机制理解，以及对疾病阶段靶点和给药策略的精心选择，可能克服这些限制，并使HDTs得以开发成为有效的结核病辅助治疗选择。
