Mitochondrial instruction of antiviral immune responses in macrophages

巨噬细胞是一种先天免疫细胞，几乎存在于人体的每一个组织中。这些高度异质的细胞调节炎症、宿主防御和动态平衡功能，包括组织重塑和修复。它们还表达广泛的模式识别受体(PRR)，识别病原体和损伤相关的分子模式(PAMP和DAMP)分子。这种与生俱来的识别能力激活了组织巨噬细胞，使它们能够对局部和全身的干扰做出快速反应。然而，这些反应必须受到严格的调控，以限制破坏性炎症和维持组织内环境的稳定。线粒体已成为先天免疫功能的中心调节器。这种调节是通过线粒体结构和线粒体代谢产物通量的动态调节来实现的。虽然很明显，线粒体代谢的重新连接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器功能方面的具体作用仍未完全确定。我的研究项目试图了解PRR对病毒配体的先天感知如何重新连接线粒体新陈代谢，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连接作为早期的变阻器来调节病原体特异性的免疫反应，这种免疫反应是基于局部组织微环境而优化的。为了验证这一假设，我们将：1)表征线粒体重连在驱动抗病毒免疫反应中的作用2)研究营养物质的可获得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拟议的工作将解决在理解细胞代谢如何调节抗病毒免疫反应方面的关键空白，并将为组织微环境如何调节这一调控提供关键的见解。我们期望确定可用于微调抗病毒反应的组织特异性生化靶点，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.