Department of Pathology, New York University School of Medicine, New York, NY, United States.
Front Cell Infect Microbiol. 2019 Aug 21;9:299. doi: 10.3389/fcimb.2019.00299. eCollection 2019.
Globally, tuberculosis (TB) has reemerged as a major cause of morbidity and mortality, despite the use of the BCG vaccine and intensive attempts to improve upon BCG or develop new vaccines. Two lacunae in our understanding of the ()-host pathogenesis have mitigated the vaccine efforts; the bacterial-host interaction that enables successful establishment of primary infection and the correlates of protection against TB. The vast majority of vaccine efforts are based on the premise that cell-mediated immunity (CMI) is the predominating mode of protection against TB. However, studies in animal models and in humans demonstrate that post-infection, a period of several weeks precedes the initiation of CMI during which the few inhaled bacteria replicate dramatically and disseminate systemically. The "Trojan Horse" mechanism, wherein is phagocytosed and transported across the alveolar barrier by infected alveolar macrophages has been long postulated as the sole, primary :host interaction. In the current review, we present evidence from our studies of transcriptional profiles of in sputum as it emerges from infectious patients where the bacteria are in a quiescent state, to its adaptations in alveolar epithelial cells where the bacteria transform to a highly replicative and invasive phenotype, to its maintenance of the invasive phenotype in whole blood to the downregulation of invasiveness upon infection of epithelial cells at an extrapulmonary site. Evidence for this alternative mode of infection and dissemination during primary infection is supported by cell-based, and transcriptional studies from multiple investigators in recent years. The proposed alternative mechanism of primary infection and dissemination across the alveolar barrier parallels our understanding of infection and dissemination of other Gram-positive pathogens across their relevant mucosal barriers in that barrier-specific adhesins, toxins, and enzymes synergize to facilitate systemic establishment of infection prior to the emergence of CMI. Further exploration of this :non-phagocytic cell interaction can provide alternative approaches to vaccine design to prevent infection with and not only decrease clinical disease but also decrease the overwhelming reservoir of latent TB infection.
全球范围内，尽管使用了卡介苗（BCG）疫苗并进行了强化努力以改进 BCG 或开发新疫苗，但结核病（TB）重新成为发病率和死亡率的主要原因。我们对（细菌-宿主）发病机制的理解存在两个空白，这削弱了疫苗的效果；细菌-宿主相互作用使原发性感染得以成功建立，而对 TB 的保护相关性也是如此。绝大多数疫苗工作都基于这样一个前提，即细胞介导的免疫（CMI）是预防 TB 的主要模式。然而，动物模型和人类研究表明，感染后，在开始产生 CMI 之前，有几周的时间，在此期间，吸入的细菌数量会急剧增加并在全身扩散。“特洛伊木马”机制，即被感染的肺泡巨噬细胞吞噬和运送到肺泡屏障，长期以来一直被认为是唯一的主要细菌-宿主相互作用。在当前的综述中，我们提出了从我们对传染性患者痰液中出现的细菌的转录谱研究中获得的证据，这些细菌处于静止状态，到其在肺泡上皮细胞中的适应，在这些细胞中，细菌转变为高度复制和侵袭性表型，到其在整个血液中维持侵袭性表型，再到在肺外部位感染上皮细胞时侵袭性的下调。近年来，多位研究人员的细胞基础和转录研究为这种原发性感染和传播的替代模式提供了证据。这种原发性感染和跨肺泡屏障传播的替代机制与我们对其他革兰氏阳性病原体通过其相关黏膜屏障的感染和传播的理解相平行，因为屏障特异性黏附素、毒素和酶协同作用，在 CMI 出现之前，促进了全身性感染的建立。进一步探索这种非吞噬细胞相互作用可以为预防结核分枝杆菌感染提供疫苗设计的替代方法，不仅可以减少临床疾病，还可以减少潜伏性结核感染的巨大储存库。
