Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Immunol Rev. 2021 May;301(1):62-83. doi: 10.1111/imr.12951. Epub 2021 Feb 9.
Upon infection, mycobacteria, such as Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria (NTM), are recognized by host innate immune cells, triggering a series of intracellular processes that promote mycobacterial killing. Mycobacteria, however, have developed multiple counter-strategies to persist and survive inside host cells. By manipulating host effector mechanisms, including phagosome maturation, vacuolar escape, autophagy, antigen presentation, and metabolic pathways, pathogenic mycobacteria are able to establish long-lasting infection. Counteracting these mycobacteria-induced host modifying mechanisms can be accomplished by host-directed therapeutic (HDT) strategies. HDTs offer several major advantages compared to conventional antibiotics: (a) HDTs can be effective against both drug-resistant and drug-susceptible bacteria, as well as potentially dormant mycobacteria; (b) HDTs are less likely to induce bacterial drug resistance; and (c) HDTs could synergize with, or shorten antibiotic treatment by targeting different pathways. In this review, we will explore host-pathogen interactions that have been identified for Mtb for which potential HDTs impacting both innate and adaptive immunity are available, and outline those worthy of future research. We will also discuss possibilities to target NTM infection by HDT, although current knowledge regarding host-pathogen interactions for NTM is limited compared to Mtb. Finally, we speculate that combinatorial HDT strategies can potentially synergize to achieve optimal mycobacterial host immune control.
在感染后，分枝杆菌（如结核分枝杆菌（Mtb）和非结核分枝杆菌（NTM））被宿主固有免疫细胞识别，触发一系列促进分枝杆菌杀伤的细胞内过程。然而，分枝杆菌已经开发出多种对抗策略来在宿主细胞内持续存在和生存。通过操纵宿主效应机制，包括吞噬体成熟、空泡逃逸、自噬、抗原呈递和代谢途径，致病性分枝杆菌能够建立持久的感染。通过宿主定向治疗（HDT）策略可以对抗这些分枝杆菌诱导的宿主修饰机制。与传统抗生素相比，HDT 具有几个主要优势：（a）HDT 可有效对抗耐药和敏感细菌，以及潜在休眠的分枝杆菌；（b）HDT 不太可能诱导细菌耐药性；（c）HDT 可以通过靶向不同途径与抗生素协同作用或缩短抗生素治疗时间。在这篇综述中，我们将探讨已确定的针对 Mtb 的宿主-病原体相互作用，其中有针对先天和适应性免疫的潜在 HDT 可用，并概述那些值得进一步研究的相互作用。我们还将讨论通过 HDT 靶向 NTM 感染的可能性，尽管与 Mtb 相比，目前对 NTM 的宿主-病原体相互作用的了解有限。最后，我们推测组合 HDT 策略可能会协同作用，以实现最佳的分枝杆菌宿主免疫控制。
