Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, United States of America.
Hackensack Meridian School of Medicine, Department of Medical Sciences, Nutley, New Jersey, United States of America.
PLoS Pathog. 2024 Oct 9;20(10):e1012595. doi: 10.1371/journal.ppat.1012595. eCollection 2024 Oct.
Chronic tuberculosis (TB) disease, which requires months-long chemotherapy with multiple antibiotics, is defined by diverse pathological manifestations and bacterial phenotypes. Targeting drug-tolerant bacteria in the host is critical to achieving a faster and durable cure for TB. In order to facilitate this field of research, we need to consider the physiology of persistent MTB during infection, which is often associated with the nonreplicating (NR) state. However, the traditional approach to quantifying bacterial burden through colony enumeration alone only informs on the abundance of live bacilli at the time of sampling, and provides an incomplete picture of the replicative state of the pathogen and the extent to which bacterial replication is balanced by ongoing cell death. Modern approaches to profiling bacterial replication status provide a better understanding of inter- and intra-population dynamics under different culture conditions and in distinct host microenvironments. While some methods use molecular markers of DNA replication and cell division, other approaches take advantage of advances in the field of microfluidics and live-cell microscopy. Considerable effort has been made over the past few decades to develop preclinical in vivo models of TB infection and some are recognized for more closely recapitulating clinical disease pathology than others. Unique lesion compartments presenting different environmental conditions produce significant heterogeneity between Mycobacterium tuberculosis populations within the host. While cellular lesion compartments appear to be more permissive of ongoing bacterial replication, caseous foci are associated with the maintenance of M. tuberculosis in a state of static equilibrium. The accurate identification of nonreplicators and where they hide within the host have significant implications for the way novel chemotherapeutic agents and regimens are designed for persistent infections.
慢性结核病（TB）需要数月的多种抗生素化疗，其病理学表现和细菌表型多种多样。靶向宿主中的耐药菌对于实现结核病的更快和更持久治愈至关重要。为了促进这一研究领域的发展，我们需要考虑感染期间持续 MTB 的生理学，这通常与非复制（NR）状态有关。然而，通过菌落计数来定量细菌负荷的传统方法只能反映采样时活细菌的丰度，不能全面了解病原体的复制状态以及细菌复制与持续细胞死亡之间的平衡程度。现代方法可用于分析细菌复制状态，从而更好地了解不同培养条件下和不同宿主微环境中的种间和种内动态。虽然一些方法使用 DNA 复制和细胞分裂的分子标记，但其他方法则利用微流控和活细胞显微镜领域的进展。在过去几十年中，人们为开发结核病感染的临床前体内模型做出了相当大的努力，其中一些模型比其他模型更能重现临床疾病病理学。不同的病变部位呈现出不同的环境条件，导致宿主内结核分枝杆菌种群之间存在显著的异质性。虽然细胞病变部位似乎更有利于持续的细菌复制，但干酪样病灶与结核分枝杆菌在静态平衡状态下的维持有关。准确识别非复制者及其在宿主内的藏身之处，对设计针对持续感染的新型化学治疗剂和方案具有重要意义。
