A genetically modulated Toll-like receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To investigate innate immune functions, 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 fully convalescent children months after MIS-C recovery. When we investigated the genetic background of patients in relation to TLR responsiveness, we found that cells from MIS-C children carrying rare heterozygous variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Moreover, these rare LYST variant heterozygous carriers tended to exhibit unfavorable clinical laboratory indicators of inflammation, including more profound lymphopenia. The results of our observational study have several implications. First, TLR hyporesponsiveness may be associated with hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands. Second, TLR hyporesponsiveness during MIS-C may be protective, since LYST variant heterozygous carriers exhibited reduced TLR hyporesponsiveness and unfavorable clinical laboratory indicators of inflammation. Thus, links may exist between genetic background, ability to establish a refractory immune state, and MIS-C clinical spectrum. Third, the possibility exists that prolonged TLR hyporesponsiveness is one of the mechanisms driving long coronavirus disease (COVID), which highlights the need to monitor long-term consequences of MIS-C.

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Publication Details

Journal
The Journal of Immunology
Published
2025-03-01
DOI
https://doi.org/10.1093/jimmun/vkaf006
Citations
5
Primary Topic
Kawasaki Disease and Coronary Complications
Type
article
Field-Weighted Citation Impact
10.03

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article

A genetically modulated Toll-like receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome

Christian Suarez, Jason Roy, Myriam Casseus, Daniel B. Horton et al.
5 citations
The Journal of Immunology
Kawasaki Disease and Coronary Complications
10.03
article

A genetically modulated Toll-like receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome

Christian Suarez, Jason Roy, Myriam Casseus, Daniel B. Horton, Aalok R. Singh, William S. Cuddy, John K. Kuster, Hülya Bükülmez, Rahul Ukey, J Rivera, Yukiko Kimura, Jane C. Burns, Abhilasha Madhvi, Tracy Andrews, Weizhen Ji, David C. Kaelber, Maria Laura Gennaro, Saquib A. Lakhani, Lawrence C. Kleinman, Ioannis E. Michailidis, Benjamin Richlin, Sandra Moroso-Fela, Rehan Khan, Uzma Hasan, Sunanda Gaur, Usha Ganapathi
article en
5 citations

Abstract

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To investigate innate immune functions, 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 fully convalescent children months after MIS-C recovery. When we investigated the genetic background of patients in relation to TLR responsiveness, we found that cells from MIS-C children carrying rare heterozygous variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Moreover, these rare LYST variant heterozygous carriers tended to exhibit unfavorable clinical laboratory indicators of inflammation, including more profound lymphopenia. The results of our observational study have several implications. First, TLR hyporesponsiveness may be associated with hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands. Second, TLR hyporesponsiveness during MIS-C may be protective, since LYST variant heterozygous carriers exhibited reduced TLR hyporesponsiveness and unfavorable clinical laboratory indicators of inflammation. Thus, links may exist between genetic background, ability to establish a refractory immune state, and MIS-C clinical spectrum. Third, the possibility exists that prolonged TLR hyporesponsiveness is one of the mechanisms driving long coronavirus disease (COVID), which highlights the need to monitor long-term consequences of MIS-C.

The Journal of ImmunologyVol. 214(3)
Rutgers, The State University of New Jersey (US), Saint Barnabas Medical Center (US), MetroHealth (US), Hackensack University Medical Center (US), New York Medical College (US), Touro College (US), Johnson University (US), Yale University (US), University of California San Diego (US), Rady Children's Hospital-San Diego (US), Maria Fareri Children's Hospital (US), Environmental and Occupational Health Sciences Institute (US), Hackensack Meridian Health (US), Case Western Reserve University (US)
National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences
Good health and well-being
Openalex Percentile: Top 2%
Kawasaki Disease and Coronary Complications
10.03
DOIOpen Access PDFOpenAlex
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