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

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。线粒体功能也与感染细胞对病毒病原体的抵抗力和先天免疫反应的调节有机械联系。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重要调节剂，T细胞的代谢适应在T细胞介导的免疫中起着至关重要的作用。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开关或调节抗病毒反应，如IFN产生或IFN- i /IFN- ii介导的效应功能，其机制尚不清楚。利用水疱性口炎病毒（VSV）模型系统的初步研究结果表明，线粒体内膜结构的改变可以调节先天免疫效应功能并减少病毒复制。具体来说，缺乏MIC60的细胞表现出比对照细胞更少的病毒复制。MIC60是“线粒体接触位点和嵴组织系统”（MICOS）复合体的核心亚基，是嵴连接（CJ）和嵴膜形态发生所必需的。此外，利用淋巴细胞性脉络丛脑膜炎病毒（LCMV）系统的研究发现，MIC60缺失的T细胞表现出IFN-II产生减少，导致T细胞中MIC60缺失小鼠的效应功能降低和病毒载量增加。因此，拟开展的研究项目将探讨动态线粒体膜重塑在抗病毒效应物功能中的作用。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ifn -i介导的抗病毒效应功能及其调控的细胞代谢。抑制线粒体内膜重塑作为干扰素-α/β受体/IFNγ受体（IFNAR/IFNγ r）信号传导下游的抗病毒效应机制将被研究。此外，MIC60在线粒体膜重塑和t细胞效应机制代谢适应中的作用将被研究。在急性和慢性LCMV感染期间，T细胞特异性缺乏MIC60的小鼠将监测T细胞效应功能，包括IFN-II的产生和LCMV感染的结果。综上所述，本研究将揭示MICOS复合物介导的线粒体内膜重塑与多种抗病毒效应机制的相互作用。

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.