Tuberculosis Research Program at the Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia.
The University of Sydney, Faculty of Medicine and Health & Marie Bashir Institute, Camperdown, NSW 2050, Australia.
Pathog Dis. 2020 Mar 1;78(2). doi: 10.1093/femspd/ftaa015.
Mycobacteria have co-evolved with their hosts resulting in pathogens adept at intracellular survival. Pathogenic mycobacteria actively manipulate infected macrophages to drive granuloma formation while subverting host cell processes to create a permissive niche. Granuloma residency confers phenotypic antimicrobial resistance by physically excluding or neutralising antibiotics. Host-directed therapies (HDTs) combat infection by restoring protective immunity and reducing immunopathology independent of pathogen antimicrobial resistance status. This review covers innovative research that has discovered 'secondary' symptoms of infection in the granuloma stroma are actually primary drivers of infection and that relieving these stromal pathologies with HDTs benefits the host. Advances in our understanding of the relationship between tuberculosis and the host vasculature, haemostatic system and extracellular matrix reorganisation are discussed. Preclinical and clinical use of HDTs against these stromal targets are summarised.
分枝杆菌与其宿主共同进化，导致病原体善于在细胞内生存。致病性分枝杆菌积极地操纵受感染的巨噬细胞来驱动肉芽肿的形成，同时颠覆宿主细胞的过程来创造一个允许的小生境。肉芽肿的驻留通过物理排斥或中和抗生素来赋予表型抗微生物药物耐药性。宿主定向治疗（HDTs）通过恢复保护性免疫和减少免疫病理而不依赖于病原体抗微生物药物耐药性来对抗感染。这篇综述涵盖了创新性的研究，该研究发现肉芽肿基质中的“次要”感染症状实际上是感染的主要驱动因素，并且用 HDTs 缓解这些基质病理学对宿主有益。讨论了我们对结核分枝杆菌与宿主脉管系统、止血系统和细胞外基质重组之间关系的理解的进展。总结了针对这些基质靶点的 HDTs 的临床前和临床应用。
