Mitochondrial instruction of antiviral immune responses in macrophages

巨噬细胞是几乎在身体的每个组织中发现的先天免疫细胞。这些高度异质性的细胞调节炎症、宿主防御和稳态功能，包括组织重塑和修复。它们还表达广泛的模式识别受体（PRR），其识别病原体和损伤相关分子模式（PAMP和DAMP）分子。这种先天识别激活组织巨噬细胞，使它们能够迅速响应局部和全身的扰动。然而，这些反应必须严格调节，以限制破坏性炎症并维持组织稳态。 线粒体已经成为先天免疫功能的中心调节器。这种调节是由线粒体结构的动态调节和线粒体代谢物的通量介导的。虽然很明显，线粒体代谢的重新布线是满足细胞的生物能量和生物合成需求所必需的，但它们在调节抗病毒免疫效应子功能中的特定作用仍然没有完全表征。 我的研究项目旨在了解PRR对病毒配体的先天感知如何重新连接线粒体代谢，以及这种重新连接如何有助于组织特异性抗病毒反应的发展。我们假设线粒体代谢的重新布线作为早期变阻器来调节病原体特异性免疫应答，其基于局部组织微环境进行优化。 为了验证这个假设，我们将： 1)描述线粒体重新布线在驱动抗病毒免疫应答中的作用 2)研究营养物质的可用性如何影响线粒体相关的抗病毒免疫反应 3)评估大脑微环境如何影响线粒体相关的抗病毒免疫反应 我们提出的工作将解决理解细胞代谢如何调节抗病毒免疫反应的关键差距，并将提供组织微环境如何调节这种调节的关键见解。我们希望确定组织特异性生化靶点，可用于微调抗病毒反应，这将对开发新的免疫疗法和提高疫苗效力具有重要意义。

Macrophages are innate immune cells found in nearly every tissue of the body. These highly heterogeneous cells regulate inflammation, host defense and homeostatic functions including tissue remodeling and repair. They also express a wide range of pattern recognition receptors (PRR) that recognize pathogen and damage associated molecular pattern (PAMP and DAMP) molecules. This innate recognition activates tissue macrophages, which allows them to respond rapidly to local and systemic perturbations. However, these responses must be tightly regulated to limit damaging inflammation and to maintain tissue homeostasis. Mitochondria have emerged as a central regulator of innate immune function. This regulation is mediated by the dynamic modulation of mitochondrial structure and the flux of mitochondrial metabolites. While it is clear that rewiring of mitochondrial metabolism is required to meet the bioenergetic and biosynthetic demands of the cell, their specific role in regulating antiviral immune effector functions remains incompletely characterized. My research program seeks to understand how innate sensing of viral ligands by PRR rewires mitochondrial metabolism and how this rewiring contributes to the development of tissue specific antiviral responses. We hypothesize that rewiring of mitochondrial metabolism acts as an early rheostat to regulate pathogen specific immune responses, which are optimized based on the local tissue microenvironment. To test this hypothesis we will: 1) Characterize the role of mitochondrial rewiring in driving antiviral immune responses 2) Examine how nutrient availability affects mitochondrial associated antiviral immune responses 3) Evaluate how the brain microenvironment affects mitochondrial associated antiviral immune responses Our proposed work will address key gaps in understanding how cellular metabolism regulates antiviral immune responses and will provide critical insights into how the tissue microenvironment modulates this regulation. We expect to identify tissue specific biochemical targets that can be used to fine tune antiviral responses, which will have important implications for the development of new immunotherapies and to improve vaccine efficacy.