Role of mitochondrial inner membrane organization during anti-viral effector functions

线粒体内膜组织在抗病毒效应功能中的作用

• 批准号: 517911415
• 负责人: Professor Dr. Philipp Alexander Lang, Ph.D.
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/517911415?language=en
• 关键词: Role; mitochondrial; inner; membrane; organization

Viral infections are a global health problem. Interferons (IFNs) are one of the most potent anti-viral defense mechanisms known. Mitochondrial functions are also mechanistically linked to the resistance of infected cells against viral pathogens and to modulation of innate immune responses. Moreover, antiviral effector T cells identify and destroy virus-infected cells. It is known that the ultrastructure of the mitochondrial inner membrane is a crucial modulator of cellular energy metabolism and that metabolic adaptations in T cells play a crucial role in T cell–mediated immunity. However, the role of the mitochondrial inner membrane ultrastructure and its dynamic remodeling in infected cells and in effector T cells, e.g., to undergo necessary metabolic switches or to modulate antiviral responses such as IFN production or IFN-I/IFN-II–mediated effector functions, is mechanistically not understood. Preliminary findings using the vesicular stomatitis virus (VSV) model system suggest that alteration of the inner mitochondrial membrane architecture can modulate innate immune effector functions and reduce viral replication. Specifically, cells lacking MIC60, a core subunit of the ‘Mitochondrial contact site and cristae organizing system’ (MICOS) complex required for cristae junction (CJ) and cristae membrane morphogenesis, show less viral replication than do control cells. Furthermore, studies using the lymphocytic choriomeningitis virus (LCMV) system have found that MIC60-deficient T cells exhibit reduced IFN-II production, resulting in reduced effector function and increased viral load in mice lacking MIC60 in T cells. Accordingly, the proposed research project will investigate the role of dynamic mitochondrial membrane remodeling during antiviral effector functions. Specific aims will be to characterize the structure and the dynamics of the mitochondrial inner membrane in virus-infected cells and the cellular metabolism in response to IFN-I–mediated antiviral effector function and its regulation. Inhibition of remodeling of the inner mitochondrial membrane as an antiviral effector mechanism downstream of interferon-α/β receptor/IFNγ receptor (IFNAR/IFNγR) signaling will be investigated. Moreover, the role of MIC60 in remodeling the mitochondrial membrane and metabolic adaptations for T-cell effector mechanisms will be investigated. T-cell effector functions, including IFN-II production and the outcome of LCMV infection, will be monitored in mice specifically lacking MIC60 in T cells during acute and chronic LCMV infection. In conclusion, the proposed research project will decipher the interplay between mitochondrial inner membrane remodeling mediated by the MICOS complex and the functions of various antiviral effector mechanisms.

病毒感染是一个全球性的健康问题。干扰素（IFN）是已知的最有效的抗病毒防御机制之一。线粒体功能也与受感染细胞对病毒病原体的抗性和先天免疫应答的调节机制相关。此外，抗病毒效应T细胞识别并破坏病毒感染的细胞。众所周知，线粒体内膜的超微结构是细胞能量代谢的关键调节剂，并且T细胞中的代谢适应在T细胞介导的免疫中起关键作用。然而，线粒体内膜超微结构的作用及其在感染细胞和效应T细胞中的动态重塑，例如，进行必要的代谢转换或调节抗病毒应答如IFN产生或IFN-1/IFN-Ⅱ介导的效应子功能的机制尚不清楚。使用水泡性口炎病毒（VSV）模型系统的初步研究结果表明，改变线粒体内膜结构可以调节先天免疫效应功能，减少病毒复制。具体而言，缺乏MIC 60的细胞，即嵴连接（CJ）和嵴膜形态发生所需的“线粒体接触位点和嵴组织系统”（MICOS）复合物的核心亚基，显示出比对照细胞更少的病毒复制。此外，使用淋巴细胞性脉络丛脑膜炎病毒（LCMV）系统的研究发现，MIC 60缺陷型T细胞表现出IFN-II产生减少，导致T细胞中缺乏MIC 60的小鼠的效应子功能降低和病毒载量增加。因此，拟议的研究项目将研究动态线粒体膜重塑在抗病毒效应功能中的作用。具体目标将是表征病毒感染细胞中线粒体内膜的结构和动力学以及响应于IFN-I介导的抗病毒效应子功能及其调节的细胞代谢。将研究作为干扰素-α/β受体/IFNγ受体（IFNAR/IFNγR）信号传导下游的抗病毒效应机制的线粒体内膜重塑抑制。此外，将研究MIC 60在重塑线粒体膜和T细胞效应机制的代谢适应中的作用。在急性和慢性LCMV感染期间，将在T细胞中特异性缺乏MIC 60的小鼠中监测T细胞效应子功能，包括IFN-II产生和LCMV感染的结果。总之，拟议的研究项目将破译由MICOS复合物介导的线粒体内膜重塑与各种抗病毒效应机制的功能之间的相互作用。