Metabolism, infection and immunity in inborn errors of mitochondrial metabolism

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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.