Department of Microbial Pathogenesis and Immunology, Texas A&M Health, College of Medicine, Bryan, Texas, USA.
Department of Microbial Pathogenesis and Immunology, Texas A&M Health, College of Medicine, Bryan, Texas, USA
Infect Immun. 2021 Mar 17;89(4). doi: 10.1128/IAI.00687-20.
Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for cross talk or synergy between bacterium- and mitochondrion-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking, and intriguing, in the context of infection with the intracellular bacterial pathogen (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages, leading to metabolic changes and triggering potent innate immune responses. Research from our laboratories and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyperactivating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrion-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.
在过去的十年中，我们了解到受损的线粒体激活了许多相同的固有免疫途径，这些途径进化而来，用于感知和应对细胞内病原体。这些共同的反应包括细胞质核酸感应和 I 型干扰素（IFN）表达、导致细胞焦亡的炎性小体激活，以及选择性自噬（当线粒体为货物时称为线粒体自噬）。由于线粒体曾经是细菌，因此细胞对线粒体和细菌配体的反应之间存在相似之处并不完全出人意料。然而，在感染过程中，细菌和线粒体驱动的固有免疫反应之间的串扰或协同作用的潜力仍知之甚少。这种相互作用在细胞内细菌病原体（Mtb）感染的背景下尤为引人注目和有趣。多项研究表明，Mtb 感染和/或特定的 Mtb 毒力因子在破坏巨噬细胞中线粒体网络方面发挥作用，导致代谢变化并引发强烈的固有免疫反应。我们实验室和其他实验室的研究表明，线粒体基因的突变通过过度激活固有反应或在错误的时间激活它们，可能会加剧分枝杆菌病的严重程度。事实上，越来越多的证据支持这样一种模式，即不同的线粒体缺陷或突变以不同的方式改变 Mtb 感染的结果。通过综合本综述中的当前文献，我们希望深入了解驱动线粒体依赖性免疫极化的分子机制及其后果，以便我们能够更好地预测结核病患者的结局，并开发旨在纠正这些失衡的宿主导向治疗方法。
