Host responses to Mycobacterium infection in Zebrafish

肉芽肿是结核病的标志性病理结构。这种富含巨噬细胞的复杂免疫结构可以保护宿主，但也可以被分枝杆菌用于生长和扩张。结核病的一个关键致病事件是肉芽肿坏死，它增加了细菌的生长、患者的发病率和传播，从而维持了结核病的全球负担。利用斑马鱼幼虫结核病模型，我们已经确定了多种遗传驱动的宿主失调，这些失调导致早期肉芽肿加速坏死，通过不同的先天免疫途径。我们确定了细菌毒力决定因素，这些决定因素可以利用这些宿主漏洞来加剧坏死。在这项提案中，我们将在先天免疫的背景下研究三种不同的早期肉芽肿坏死途径。药物诱导的肿瘤坏死因子缺乏是众所周知的结核病危险因素，我们将调查它是如何导致肉芽肿坏死的。我们将研究我们的假设，即肿瘤坏死因子的主要作用是作为巨噬细胞的促生存因子，阻止有利于分枝杆菌的细胞凋亡。我们将研究过量的肿瘤坏死因子(我们已经证明会导致人类对结核病的易感性)是如何被分枝杆菌通过涉及肿瘤坏死受体2的不同途径来引起坏死的。我们将继续研究我们的发现，即mTOR促进了线粒体代谢程序，该程序专门保护线粒体免受分枝杆菌毒力决定因素ESAT-6的线粒体破坏效应。我们将了解低氧诱导因子1(HIF-1)，一种宿主抵抗因子，是如何在结核肉芽肿中结构性表达时致病的。通过对分枝杆菌发病机制的研究，我们希望对免疫信号、免疫代谢和线粒体生物学有更深入的了解。

The granuloma is the hallmark pathological structure in tuberculosis (TB). This macrophage-rich complex immune structure can be host-protective but can also be co-opted by mycobacteria for growth and expansion. A critical pathogenic event in TB is granuloma necrosis, which increases bacterial growth, patient morbidity and transmission, thus sustaining the global burden of TB. Using the zebrafish larval model of TB, we have identified multiple genetically-driven host dysregulations that lead to accelerated necrosis of the early granuloma through different innate immune pathways. We identified bacterial virulence determinants that can co-opt these host vulnerabilities to accentuate necrosis. In this proposal, we will investigate three distinct pathways of early granuloma necrosis in the context of innate immunity. Medically induced TNF deficiency is a well-known TB risk factor, and we will investigate how it causes granuloma necrosis. We will investigate our hypothesis that TNF’s dominant effect is as a macrophage pro- survival factor, preventing mycobacterium-beneficial apoptosis. We will study how excess TNF, which we have shown to cause human TB susceptibility, is co-opted by mycobacteria to cause necrosis through a distinct pathway that involves TNF receptor 2. We will pursue our findings that mTOR facilitates a mitochondrial metabolic program that specifically protects against the mitochondrion-damaging effect of the mycobacterial virulence determinant, ESAT-6. We will understand how hypoxia inducible factor 1 (HIF-1), a host resistance factor, becomes pathogenic when expressed constitutively in TB granulomas. Through the lens of mycobacterial pathogenesis, we hope to glean insights into immune signaling, immunometabolism and mitochondrial biology.