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Innate Immunity: Mechanisms and Modulation | EK39


EK39-EPOSTER-CAVOUNIDIS-ATHENA - Human HPS1 deficiency leads to impaired anti-microbial activity and inflammation


Apr 12, 2021 12:00am ‐ Apr 12, 2021 12:00am

Description

Human HPS1 deficiency leads to impaired anti-microbial activity and inflammation Athena Cavounidis1, Sumeet Pandey1, Melania Capitani1, Dominik Aschenbrenner1, Seunghee Kim-Schulze2, Esther A. Torres3, Georgina Berridge4, Dermot P.B. McGovern5, Benedikt Kessler4, Roman Fischer4, Fiona Powrie1, 6, Bernadette R. Gochuico7, William A. Gahl7, Louis Cohen8,$ and Holm H. Uhlig1, 9, 10,$ 1Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 2Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA 3University of Puerto Rico School of Medicine, Puerto Rico, USA 4Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK 5F. Widjaja Foundation Inflammatory Bowel and Immunobiology Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA 6Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK 7Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA 8Icahn School of Medicine at Mount Sinai, New York, NY, USA 9Department of Paediatrics, University of Oxford, Oxford, UK 10Oxford NIHR Biomedical Research Centre, Oxford, UK $These authors contributed equally Mendelian diseases that present with immune-mediated disorders can provide insights into the molecular mechanisms that drive inflammation. Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking involving the BLOC-3 complex. The presence of inflammatory complications such as Crohn’s disease-like inflammation and lung fibrosis in these patients remains enigmatic. We use mass cytometry on peripheral blood and serum proteomics to identify an inflammatory signature dominated by cytokine dysregulation. HPS-1 patient monocyte-derived macrophages have alterations in lipid metabolism, consistent with the ceroid lipofuscin accumulation seen in patients. Using stimulation experiments and lysosomal proteomics we show that HPS1 deficiency causes aberrant mTOR signaling. This pathogenic circuit translates into hampered bacterial clearance, which can be rescued with mTORC1 inhibition. We reveal that a pathogenic lipid-mTOR signaling circuit acts as a metabolic checkpoint for defective anti-microbial activity. This mechanism may be relevant to the complex pathology of HPS1 patients featuring macrophage lipid accumulation, granuloma formation, defective anti-microbial activity and tissue inflammation. Lastly, this circuit may be present in a wider group of disorders with defective lipid metabolism and cholesterol accumulation.

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