Browsing by Author "Zhang, Yu"

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    Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19
    (2022) Sacco , Keith; Castagnoli , Riccardo; Vakkilainen, Svetlana; Liu, Can; Delmonte, Ottavia M.; Oguz, Cihan; Kaplan, Ian M.; Alehashemi, Sara; Burbelo, Peter D.; Bhuyan, Farzana; Jesus, Adriana A.; Dobbs , Kerry; Rosen, Lindsey B.; Cheng, Aristine; Shaw, Elana; Vakkilainen, Mikko S.; Pala , Francesca; Lack, Justin; Zhang, Yu; Fink, Danielle L.; Oikonomou, Vasileios; Snow , Andrew L.; Dalgard, Clifton L.; Chen, Jinguo; Sellers, Brian A.; Montealegre Sanchez, Gina A.; Barron, Karyl; Rey-Jurado, Emma; Vial, Cecilia; Poli, Cecilia; Licari, Amelia; Montagna, Daniela; Marseglia, Gian Luigi
    Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n= 110) and MIS-C (n= 76), along with pediatric healthy controls (pHCs; n= 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy
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    Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19
    (2022) Carmona, Carmelo; Zhang, Yu; Dobbs, Kerry; Markowitz, Tovah; Dalgard, Clifton; Oler, Andrew; Claybaugh, Dillon; Draper, Deborah; Truong, Meng; Delmonte, Ottavia; Licciardi, Francesco; Ramenghi, Ugo; Crescenzio, Nicoletta; Imberti, Luisa; Sottini, Alessandra; Quaresima, Virginia; Fiorini, Chiara; Discepolo, Valentina; Lo Vecchio, Andrea; Guarino, Alfredo; Pierri, Luca; Catzola, Andrea; Biondi, Andrea; Bonfanti, Paolo; Poli, Cecilia; Espinosa, Yasmin; Astudillo, Camila; Rey, Emma; Vial, Cecilia; De la Cruz, Javiera; González, Ricardo; Pinera, Cecilia; Mays, Jacqueline; Ng, Ashley; Platt, Andrew; NIH COVID Autopsy Consortium; COVID STORM Clinicians; Drolet, Beth; Moon, John; Cowen, Edward; Kenney, Heather; Weber, Sarah; Castagnoli, Riccardo; Magliocco, Mary; Stack, Michael; Montealegre, Gina; Barron, Karyl; Fink, Danielle; Kuhns, Douglas; Hewitt, Stephen; Arkin, Lisa; Chertow, Daniel; Su, Helen; Notarangelo, Luigi; Kaplan, Mariana
    Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes," remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

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