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合免疫结构可以是宿主保护性的，但也可以被分枝杆菌选择用于生长和扩增。结核病的一个关键致病事件是肉芽肿坏死，它增加了细菌生长、患者发病率和传播，从而维持了结核病的全球负担。使用结核病的斑马鱼幼虫模型，我们已经确定了多种遗传驱动的宿主失调，通过不同的先天免疫途径导致早期肉芽肿的加速坏死。我们确定了细菌的毒力决定因素，可以增选这些主机的弱点，加重坏死。在这个建议中，我们将研究先天免疫背景下早期肉芽肿坏死的三种不同途径。医学诱导的TNF缺乏是一个众所周知的结核病危险因素，我们将研究它是如何引起肉芽肿坏死的。我们将研究我们的假设，即TNF的主要作用是作为巨噬细胞促存活因子，阻止分枝杆菌有益的细胞凋亡。我们将研究如何过量的TNF，我们已经表明，导致人类结核病的易感性，是增选分枝杆菌通过一个独特的途径，涉及TNF受体2引起坏死。我们将继续研究我们的发现，即mTOR促进线粒体代谢程序，专门保护免受分枝杆菌毒力决定因子ESAT-6的破坏作用。我们将了解缺氧诱导因子1（HIF-1），一种宿主抗性因子，如何在结核肉芽肿中组成型表达时成为致病因子。通过分枝杆菌发病机制的透镜，我们希望收集到免疫信号，免疫代谢和线粒体生物学的见解。

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.