PMID- 38370700 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240226 DP - 2024 Feb 5 TI - A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome. LID - 2024.02.02.24301686 [pii] LID - 10.1101/2024.02.02.24301686 [doi] AB - Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rare LYST variant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C. FAU - Khan, Rehan AU - Khan R AUID- ORCID: 0000-0001-6035-4159 AD - Public Health Research Institute, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ. FAU - Ji, Weizhen AU - Ji W AD - Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510. FAU - Guzman-Rivera, Jeisac AU - Guzman-Rivera J AD - Public Health Research Institute, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ. FAU - Madhvi, Abhilasha AU - Madhvi A AD - Public Health Research Institute, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ. FAU - Andrews, Tracy AU - Andrews T AD - Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ. FAU - Richlin, Benjamin AU - Richlin B AD - Pediatric Clinical Research Center, and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. FAU - Suarez, Christian AU - Suarez C AD - Pediatric Clinical Research Center, and Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. FAU - Gaur, Sunanda AU - Gaur S AD - Department of Pediatrics, Clinical Research Center, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. FAU - Cuddy, William AU - Cuddy W AD - Maria Fareri Children's Hospital, Valhalla, NY. FAU - Singh, Aalok R AU - Singh AR AD - Maria Fareri Children's Hospital, Valhalla, NY. AD - New York Medical College, Valhalla, NY. FAU - Bukulmez, Hulya AU - Bukulmez H AD - Department of Pediatrics, Division of Rheumatology, MetroHealth System, Cleveland OH. FAU - Kaelber, David AU - Kaelber D AD - Department of Pediatrics, Division of Rheumatology, MetroHealth System, Cleveland OH. AD - Center for Clinical Informatics Research and Education, MetroHealth System, Cleveland OH. AD - Department of Internal Medicine, Pediatrics, and Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland OH. FAU - Kimura, Yukiko AU - Kimura Y AD - Hackensack University Medical Center, Hackensack Meridian School of Medicine, Nutley, NJ. FAU - Ganapathi, Usha AU - Ganapathi U AD - Public Health Research Institute, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ. FAU - Michailidis, Ioannis E AU - Michailidis IE AD - Public Health Research Institute, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ. FAU - Ukey, Rahul AU - Ukey R AUID- ORCID: 0000-0002-0354-7496 AD - Public Health Research Institute, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ. FAU - Moroso-Fela, Sandra AU - Moroso-Fela S AD - Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. FAU - Kuster, John K AU - Kuster JK AD - Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510. FAU - Casseus, Myriam AU - Casseus M AD - Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. FAU - Roy, Jason AU - Roy J AD - Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ. FAU - Kleinman, Lawrence C AU - Kleinman LC AD - Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. AD - Department of Global Urban Health, Rutgers School of Public Health, Piscataway, NJ. FAU - Horton, Daniel B AU - Horton DB AUID- ORCID: 0000-0002-1831-1339 AD - Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ. AD - Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. AD - Rutgers Center for Pharmacoepidemiology and Treatment Science, Institute for Health, Health Care Policy and Aging Research, New Brunswick, NJ. FAU - Lakhani, Saquib A AU - Lakhani SA AUID- ORCID: 0000-0003-3235-3460 AD - Pediatric Genomics Discovery Program, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06510. FAU - Gennaro, Maria Laura AU - Gennaro ML AD - Public Health Research Institute, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ. AD - Department of Medicine, Rutgers New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ. LA - eng GR - R01 AI158911/AI/NIAID NIH HHS/United States GR - R33 HD105619/HD/NICHD NIH HHS/United States GR - R61 HD105619/HD/NICHD NIH HHS/United States GR - UL1 TR003017/TR/NCATS NIH HHS/United States PT - Preprint DEP - 20240205 PL - United States TA - medRxiv JT - medRxiv : the preprint server for health sciences JID - 101767986 PMC - PMC10871447 EDAT- 2024/02/19 06:43 MHDA- 2024/02/19 06:44 PMCR- 2024/02/16 CRDT- 2024/02/19 04:15 PHST- 2024/02/19 06:43 [pubmed] PHST- 2024/02/19 06:44 [medline] PHST- 2024/02/19 04:15 [entrez] PHST- 2024/02/16 00:00 [pmc-release] AID - 2024.02.02.24301686 [pii] AID - 10.1101/2024.02.02.24301686 [doi] PST - epublish SO - medRxiv [Preprint]. 2024 Feb 5:2024.02.02.24301686. doi: 10.1101/2024.02.02.24301686.