Unraveling the molecular mechanisms for COVID-19-associated encephalopathy and its immunopathology is crucial for developing effective treatments.Here,we utilized single-cell transcriptomic analysis and integrated cli...Unraveling the molecular mechanisms for COVID-19-associated encephalopathy and its immunopathology is crucial for developing effective treatments.Here,we utilized single-cell transcriptomic analysis and integrated clinical observations and laboratory examination to dissect the host immune responses and reveal pathological mechanisms in COVID-19-associated pediatric encephalopathy.We found that lymphopenia was a prominent characteristic of immune perturbation in COVID-19 patients with encephalopathy,especially those with acute necrotizing encephalopathy(AE).This was characterized a marked reduction of various lymphocytes(e.g.,CD8^(+)T and CD4^(+)T cells)and significant increases in other inflammatory cells(e.g.,monocytes).Further analysis revealed activation of multiple cell apoptosis pathways(e.g.,granzyme/perforin-,FAS-and TNF-induced apoptosis)may be responsible for lymphopenia.A systemic S100A12 upregulation,primarily from classical monocytes,may have contributed to cytokine storms in patients with AE.A dysregulated type I interferon(IFN)response was observed which may have further exacerbated the S100A12-driven inflammation in patients with AE.In COVID-19 patients with AE,myeloid cells(e.g.,monocytic myeloid-derived suppressor cells)were the likely contributors to immune paralysis.Finally,the immune landscape in COVID-19 patients with encephalopathy,especially for AE,were also characterized by NK and T cells with widespread exhaustion,higher cytotoxic scores and inflammatory response as well as a dysregulated B cell-mediated humoral immune response.Taken together,this comprehensive data provides a detailed resource for elucidating immunopathogenesis and will aid development of effective COVID-19-associated pediatric encephalopathy treatments,especially for those with AE.展开更多
基金This work was supported by grants from National Key Research and Development Program of China(Grant Nos.2021YFC2301101,2021YFC2301102)Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority(XTCX201820)+3 种基金Capital's Funds for Health Improvement and Research(No.2020-2-2094)Capital's Funds for Health Improvement and Research(2022-2-1132)Beijing Hospitals Authority's Ascent Plan(DFL20221102)Public service development and reform pilot project of Beijing Medical Research Institute(BMR2021-3).Laurence Don Wai Luu was supported by a UTS Chancellor's Postdoctoral Research Fellowship.
文摘Unraveling the molecular mechanisms for COVID-19-associated encephalopathy and its immunopathology is crucial for developing effective treatments.Here,we utilized single-cell transcriptomic analysis and integrated clinical observations and laboratory examination to dissect the host immune responses and reveal pathological mechanisms in COVID-19-associated pediatric encephalopathy.We found that lymphopenia was a prominent characteristic of immune perturbation in COVID-19 patients with encephalopathy,especially those with acute necrotizing encephalopathy(AE).This was characterized a marked reduction of various lymphocytes(e.g.,CD8^(+)T and CD4^(+)T cells)and significant increases in other inflammatory cells(e.g.,monocytes).Further analysis revealed activation of multiple cell apoptosis pathways(e.g.,granzyme/perforin-,FAS-and TNF-induced apoptosis)may be responsible for lymphopenia.A systemic S100A12 upregulation,primarily from classical monocytes,may have contributed to cytokine storms in patients with AE.A dysregulated type I interferon(IFN)response was observed which may have further exacerbated the S100A12-driven inflammation in patients with AE.In COVID-19 patients with AE,myeloid cells(e.g.,monocytic myeloid-derived suppressor cells)were the likely contributors to immune paralysis.Finally,the immune landscape in COVID-19 patients with encephalopathy,especially for AE,were also characterized by NK and T cells with widespread exhaustion,higher cytotoxic scores and inflammatory response as well as a dysregulated B cell-mediated humoral immune response.Taken together,this comprehensive data provides a detailed resource for elucidating immunopathogenesis and will aid development of effective COVID-19-associated pediatric encephalopathy treatments,especially for those with AE.
