Metabolism, infection and immunity in inborn errors of mitochondrial metabolism

我们的转化研究计划的总体目标是了解线粒体疾病儿童中宿主-病原体相互作用的机制。 项目1：感染和Leigh综合征 Leigh综合征和相关疾病患者的表征通过专门的自然史研究、线粒体代谢先天性缺陷中的代谢、感染和免疫（ClinicalTrials.gov标识符：NCT 01780168）和线粒体疾病中的急性感染（NCT 04419870）完成。通过这些临床方案，我们继续积累自然史数据，为旨在改善Leigh综合征儿童病毒感染期间临床护理的机制研究提供信息。我们继续为社区提供关于宿主-病原体相互作用，疫苗接种，感染风险缓解和Leigh综合征及相关疾病的免疫健康的指导。 过渡到临床意义，我们对MtD社区内风险缓解行为（RMBs）的调查，如论文2所述，为COVID-19大流行期间的社区反应提供了明确的一瞥。在500多个受结核病影响的家庭中，对RMBs的坚持率高得惊人，这突出表明了对预防性卫生措施的坚定承诺。他们坚定的奉献精神不仅强调了RMBs的重要性，也表明了疾病的严重程度如何影响健康行为。 此外，我们在论文#1中阐述的对有MtD儿童的家庭的疫苗态度的审查揭示了有趣的趋势。虽然对RMBs的坚持仍然强劲，但疫苗接种率显示出明确的细微差别。值得注意的是，尽管COVID-19疫苗易受感染，但对COVID-19疫苗的犹豫不决引发了关键问题。这种二分法直接要求提供关于疫苗安全性和有效性的有针对性的数据，最终导致制定强有力的政策建议。 项目2：免疫功能和Leigh综合征 我们对Leigh综合征免疫功能的研究揭示了由复杂的机制途径和特征定义的景观。论文8中记录的关键研究对PBMC进行了深入分析，明确区分了健康志愿者和MtD患者。结果是惊人的，揭示了MtD患者明确的免疫基因失调模式。炎性、IL-1、TLR和IFN特征的存在，加上下调的NK、T和B细胞相关基因集，强调了MtD中免疫景观的复杂性。性别特异性维度也浮出水面，在B、NK和T细胞亚群中观察到差异富集。我们对潜在治疗干预的探索已经深入了解了线粒体功能和免疫途径之间的直接机制相互作用。最值得注意的是，独立于感染的抗病毒I型干扰素信号传导的升高提供了线粒体功能障碍对免疫应答的影响的直接证据。 我们在抗菌免疫方面的工作阐明了氧化磷酸化（OXPHOS）缺陷与体液免疫之间的联系。通过我们的研究（论文#3），我们在患有MTD的儿童和对照中使用多重血清学，并揭示了OXPHOS缺乏对B细胞抗菌谱的影响。与对照组相比，MtD儿童显示抗菌抗体反应减弱。 此外，我们利用外周血单核细胞的单细胞RNA测序（scRNAseq）分析的研究（论文#2）强调了OXPHOS缺陷对特定免疫细胞群体的显著影响，为潜在的治疗途径提供了切实的见解。此外，我们的研究扩展到体液免疫，揭示妥协的反应和限制多克隆性抗病毒抗体库的儿童结核分枝杆菌。 除了上述工作外，我们还与免疫代谢社区合作，并为文献6、7和9中提到的多个项目做出了重大贡献。 总之，我们在破译感染动力学、风险缓解和MtD免疫功能方面的进展是变革性的。我们的多方面研究共同提供了一个生动的描述的脆弱性，反应，并在MtD领域的潜在干预措施。我们正在进行的努力不仅促进了科学理解，而且还转化为强有力的政策建议和临床见解，为受MtD影响的个人带来了实实在在的好处。

The overall goal of our translational research program is to understand the mechanisms involved in host-pathogen interactions in children with mitochondrial disease. Project 1: Infection and Leigh Syndrome The characterization of patients with Leigh Syndrome and related disorders is accomplished via dedicated natural history studies, Metabolism, Infection and Immunity in Inborn Errors of Mitochondrial Metabolism (ClinicalTrials.gov Identifier: NCT01780168) and Acute infection in Mitochondrial Disease (NCT04419870). Through these clinical protocols, we continue to accumulate natural history data that inform mechanistic studies aimed at improving clinical care during viral infection in children with Leigh Syndrome. We continue to provide guidance to the community on host-pathogen interactions, vaccination, infection risk mitigation and immune health in Leigh Syndrome and related disorders. Transitioning to clinical significance, our investigation into risk mitigation behaviors (RMBs) within the MtD community, as detailed in Paper #2, has offered a definitive glimpse into community responses during the COVID-19 pandemic. Astonishingly high adherence rates to RMBs among over 500 MtD-affected families have underscored the unwavering commitment to preventive health measures. Their steadfast dedication not only underscores the significance of RMBs but also signifies how disease severity shapes health behaviors. Furthermore, our scrutiny of vaccine attitudes among families with a child with MtD, elucidated in Paper #1, has unveiled intriguing trends. While adherence to RMBs remains robust, vaccine uptake rates have showcased definitive nuances. Notably, hesitancy towards the COVID-19 vaccine, despite the vulnerability to infection, has raised critical questions. This dichotomy serves as a direct call for targeted data on vaccine safety and effectiveness, ultimately leading to the formulation of robust policy recommendations. Project 2: Immune Function and Leigh Syndrome Our studies of immune function within Leigh Syndrome have unveiled a landscape defined by intricate mechanistic pathways and signatures. The pivotal study documented in Paper #8 engaged in an in-depth analysis of PBMCs, drawing a clear distinction between healthy volunteers and MtD patients. The outcomes have been striking, revealing unequivocal immune gene dysregulation patterns in MtD patients. The presence of inflammatory, IL-1, TLR, and IFN signatures, coupled with downregulated NK, T, and B cell-related gene sets, underscores the immune landscape intricacies in MtD. A gender-specific dimension also surfaced, with differential enrichments observed in B, NK, and T cell subsets. Our exploration of potential therapeutic interventions has yielded insights into the direct mechanistic interplay between mitochondrial function and immune pathways. Most notably, the elevation of antiviral type I interferon signaling, independent of infection, provides direct evidence of the impact of mitochondrial dysfunction on immune responses. Our work on antibacterial immunity has illuminated the connection between oxidative phosphorylation (OXPHOS) deficiency and humoral immunity. Via our study (Paper #3), we used multiplex serology in children with MTD and controls and uncovered the influence of OXPHOS deficiency on the B cell antibacterial repertoire. Children with MtD displayed diminished antibacterial antibody responses when compared to controls. Furthermore, our investigations (Paper #2) utilizing single-cell RNA sequencing (scRNAseq) analysis of peripheral blood mononuclear cells underscored the significant impact of OXPHOS deficiency on specific immune cell populations, offering tangible insights into potential therapeutic avenues. Moreover, our study extended to humoral immunity, revealing compromised responses and restricted polyclonality in the antiviral antibody repertoire of children with MtD. In addition to our work outlined above, we have also been collaborating with the immunometabolism community and have significantly contributed to multiple projects as noted in papers 6,7,and 9, as noted in the bibliography. In summation, our progress in deciphering infection dynamics, risk mitigation, and immune function in MtD has been transformative. Our multidimensional studies collectively provide a vivid portrayal of vulnerabilities, responses, and potential interventions within the realm of MtD. Our ongoing efforts not only advance scientific understanding but also translate into robust policy recommendations and clinical insights, poised to bring tangible benefits to individuals impacted by MtD.