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    Proteomic Profiling of MIS HGNC-C Patients Reveals Heterogeneity Relating to Interferon Gamma HGNC Dysregulation and Vascular Endothelial Dysfunction

    Authors: Caroline Diorio; Rawan Shraim; Laura A Vella; Josephine R Giles; Amy E Baxter; Derek A Oldridge; Scott W Canna; Sarah E Henrickson; Kevin O McNerney; Frances Balamuth; Chakkapong Burudpakdee; Jessica Lee; Tomas Leng; Alvin Farrel; Michele P Lambert; Kathleen E Sullivan; E. John Wherry; David T Teachey; Hamid Bassiri; Edward M Behrens

    doi:10.1101/2021.04.13.21255439 Date: 2021-04-20 Source: medRxiv

    Multi-system Inflammatory Syndrome in Children ( MIS HGNC-C) is a major complication of the Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2) pandemic in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock MESHD-like picture and marked inflammation MESHD. Children with MIS HGNC-C present with varying degrees of cardiovascular and hyperinflammatory symptoms MESHD. We performed a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesized that the proteome would reflect heterogeneity in hyperinflammation and vascular injury MESHD, and further identify pathogenic mediators of disease. Protein signatures demonstrated overlap between MIS HGNC-C, and the inflammatory syndromes macrophage activation syndrome MESHD ( MAS MESHD) and thrombotic microangiopathy MESHD ( TMA MESHD). We demonstrate that PLA2G2A HGNC is a key marker of MIS HGNC-C that associates with TMA MESHD. We found that IFN{gamma HGNC} responses are dysregulated in MIS HGNC-C patients, and that IFN{gamma HGNC} levels delineate clinical heterogeneity.

    Post-infectious inflammatory disease in MIS HGNC-C features elevated cytotoxicity MESHD signatures and autoreactivity that correlates with severity

    Authors: Anjali Ramaswamy; Nina N. Brodsky; Tomokazu S. Sumida; Michela Comi; Hiromitsu Asashima; Kenneth B. Hoehn; Ningshan Li; Yunqing Liu; Aagam Shah; Neal G. Ravindra; Jason Bishai; Alamzeb Khan; William Lau; Brian Sellers; Neha Bansal; Rachel Sparks; Avraham Unterman; Victoria Habet; Andrew J. Rice; Jason Catanzaro; Harsha Chandnani; Merrick Lopez; Naftali Kaminski; Charles S. Dela Cruz; John S. Tsang; Zuoheng Wang; Xiting Yan; Steven H. Kleinstein; David van Dijk; Richard W. Pierce; David A. Hafler; Carrie L. Lucas

    doi:10.1101/2020.12.01.20241364 Date: 2020-12-04 Source: medRxiv

    Multisystem inflammatory syndrome MESHD in children ( MIS HGNC-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection MESHD in otherwise healthy children. Here, we define immune abnormalities in MIS HGNC-C compared to adult COVID-19 MESHD and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS HGNC-C patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 HGNC are expanded. Consistently, we detect elevated binding of serum IgG from severe MIS HGNC-C patients to activated human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology features of MIS HGNC-C with implications for predicting and managing this SARS-CoV2-induced critical illness MESHD in children.

    Deep Immune Profiling of MIS HGNC-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19 MESHD

    Authors: Laura Vella; Josephine R. Giles; Amy E. Baxter; Derek A Oldridge; Caroline Diorio; Leticia Kuri-Cervantes; Cecile Alanio; Maria Betina Pampena; Jennifer E Wu; Zeyu Chen; Yinghui Jane Huang; Elizabeth M. Anderson; Sigrid Gouma; Kevin O. McNerney; Julie Chase; Chakkapong Burudpakdee; Jessica H. Lee; Sokratis A. Apostolidis; Alexander C. Huang; Divij Mathew; Oliva Kuthuru; Eileen C. Goodwin; Madison E. Weirick; Marcus J. Bolton; Claudia P. Arevalo; Andre Ramos; Cristina Jasen; Heather M. Giannini; Kurt DAndrea; - The UPenn COVID Processing Unit; Nuala J. Meyer; Edward M. Behrens; Hamid Bassiri; Scott E. Hensley; Sarah E. Henrickson; David T. Teachey; Michael R. Betts; E. John Wherry

    doi:10.1101/2020.09.25.20201863 Date: 2020-09-27 Source: medRxiv

    Pediatric COVID-19 MESHD following SARS-CoV-2 infection MESHD is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome MESHD in Children ( MIS HGNC-C) that can lead to vascular complications and shock, but rarely death MESHD. The immune features of MIS HGNC-C compared to pediatric COVID-19 MESHD or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric MESHD patients (pediatric COVID-19 MESHD) and patients with MIS HGNC-C. MIS HGNC-C patients had patterns of T cell-biased lymphopenia MESHD and T cell activation similar to severely ill adults, and all patients with MIS HGNC-C had SARS-CoV-2 spike PROTEIN-specific antibodies at admission. A distinct feature of MIS HGNC-C patients was robust activation of vascular patrolling CX3CR1 HGNC+ CD8 T cells that correlated with use of vasoactive medication. Finally, whereas pediatric COVID-19 MESHD patients with acute respiratory distress syndrome MESHD ( ARDS MESHD) had sustained immune activation, MIS HGNC-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non- MIS HGNC-C versus MIS HGNC-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct and implicate CD8 T cells in clinical presentation and trajectory of MIS HGNC-C.

    Serology in Children with Multisystem Inflammatory Syndrome ( MIS HGNC-C) associated with COVID-19 MESHD

    Authors: Christina A. Rostad; Ann Chahroudi; Grace Mantus; Stacey A. Lapp; Mehgan Teherani; Lisa Macoy; Bradley S. Rostad; Sarah S. Milla; Keiko M. Tarquinio; Rajit K. Basu; Carol Kao; W. Matthew Linam; Matthew G. Zimmerman; Pei-Yong Shi; Vineet D. Menachery; Matthew E. Oster; Sri Edupuganti; Evan J. Anderson; Mehul S Suthar; Jens Wrammert; Preeti Jaggi

    doi:10.1101/2020.07.10.20150755 Date: 2020-07-11 Source: medRxiv

    Objectives: We aimed to measure SARS-CoV-2 serologic responses in children hospitalized with multisystem inflammatory syndrome MESHD ( MIS HGNC-C) compared to COVID-19 MESHD, Kawasaki Disease MESHD ( KD MESHD) and other hospitalized pediatric controls. Methods: From March 17, 2020 - May 26, 2020, we prospectively identified hospitalized children at Children's Healthcare of Atlanta with MIS HGNC-C (n=10), symptomatic PCR-confirmed COVID-19 MESHD (n=10), KD MESHD (n=5), and hospitalized controls (n=4). With IRB approval, we obtained prospective and residual blood samples from these children and measured SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN (S) receptor binding domain (RBD) IgM and IgG binding antibodies by quantitative ELISA and SARS-CoV-2 neutralizing antibodies by live-virus focus reduction neutralization assay. We statistically compared the log-transformed antibody titers among groups and performed correlation analyses using linear regression. Results: All children with MIS HGNC-C had high titers of SARS-CoV-2 RBD IgG antibodies, which correlated strongly with neutralizing antibodies (R2=0.667, P<0.001). Children with MIS HGNC-C had significantly higher SARS-CoV-2 RBD IgG antibody titers (geometric mean titer [GMT] 6800, 95%CI 3495-13231) than children with COVID-19 MESHD (GMT 626, 95%CI 251-1563, P<0.001), children with KD MESHD (GMT 124, 95%CI 91-170, P<0.001) and other hospitalized pediatric controls (GMT 85 [all below assay limit of detection], P<0.001). All children with MIS HGNC-C also had detectable RBD IgM antibodies, indicating recent SARS-CoV-2 infection MESHD. RBD IgG titers correlated with erythrocyte sedimentation rate (ESR) (R2=0.512, P<0.046) and with hospital and ICU lengths of stay (R2=0.590, P=0.010). Conclusion: Quantitative SARS-CoV-2 RBD antibody titers may have a role in establishing the diagnosis of MIS HGNC-C, distinguishing it from other similar clinical entities, and stratifying risk for adverse outcomes.

    Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C)

    Authors: Conor Gruber; Roosheel Patel; Rebecca Trachman; Lauren Lepow; Fatima Amanat; Florian Krammer; Karen M. Wilson; Kenan Onel; Daniel Geanon; Kevin Tuballes; Manishkumar Patel; Konstantinos Mouskas; Nicole Simons; Vanessa Barcessat; Diane Del Valle; Samantha Udondem; Gurpawan Kang; Sandeep Gangadharan; George Ofori-Amanfo; Adeeb Rahman; Seunghee Kim-Schulze; Alexander Charney; Sacha Gnjatic; Bruce Gelb; Miriam Merad; Dusan Bogunovic

    doi:10.1101/2020.07.04.20142752 Date: 2020-07-06 Source: medRxiv

    Initially, the global outbreak of COVID-19 MESHD caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spared children from severe disease. However, after the initial wave of infections, clusters of a novel hyperinflammatory disease MESHD have been reported in regions with ongoing SARS-CoV-2 MESHD epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown. Herein, we report on the immune profiles of eight Multisystem Inflammatory Syndrome MESHD in Children ( MIS HGNC-C) cases. We document that all MIS HGNC-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with normal isotype-switching and neutralization capability. We further profiled the secreted immune response by high-dimensional cytokine assays, which identified elevated signatures of inflammation MESHD ( IL-18 HGNC and IL-6 HGNC), lymphocytic and myeloid chemotaxis and activation ( CCL3 HGNC, CCL4 HGNC, and CDCP1 HGNC) and mucosal immune dysregulation ( IL-17A HGNC, CCL20 HGNC, CCL28 HGNC). Mass cytometry immunophenotyping of peripheral blood revealed reductions of mDC1 and non-classical monocytes, as well as both NK- and T- lymphocytes, suggesting extravasation to affected tissues. Markers of activated myeloid function were also evident, including upregulation of ICAM1 HGNC and FcR1 in neutrophil and non-classical monocytes, well-documented markers in autoinflammation MESHD and autoimmunity that indicate enhanced antigen presentation and Fc-mediated responses. Finally, to assess the role for autoimmunity secondary to infection, we profiled the auto-antigen reactivity of MIS HGNC-C plasma, which revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal and immune-cell antigens. All patients were treated with anti- IL6R HGNC antibody or IVIG, which led to rapid disease resolution tracking with normalization of inflammatory markers.

    Prior infection by seasonal coronaviruses does not prevent SARS-CoV-2 infection MESHD and associated Multisystem Inflammatory Syndrome in children

    Authors: isabelle sermet; sarah temmam; christele huon; sylvie behillil; vincent gadjos; thomas bigot; thibaut lurier; delphine chretien; marija backovick; Agnes Moisan-Delaunay; flora donati; melanie albert; elsa foucaud; Bettina Mesplees; gregoire benoist; albert fayes; marc duval-arnould; celia cretolle; marina charbit; melodie aubart; Johanne Auriau; matthie lorrot; Dulanjalee Kariyawasam; laura fertita; Gilles Orliaguet; benedicte pigneur; Brigitte Bader-Meunier; coralie briand; julie toubiana; Tiffany Guilleminot; sylvie van der werf; marianne leruez-ville; marc eloit

    doi:10.1101/2020.06.29.20142596 Date: 2020-06-30 Source: medRxiv

    Background: Children have a lower rate of COVID-19 MESHD, potentially related to cross-protective immunity conferred by seasonal coronaviruses (HCoVs). We tested if prior infections with seasonal coronaviruses impacted SARS-CoV-2 infection MESHD SARS-CoV-2 infection MESHDs and related Multisystem Inflammatory Syndrome MESHD ( MIS MESHD MIS HGNC). Methods: This cross-sectional observational study in Paris hospitals enrolled 739 pauci or asymptomatic children (HOS group) plus 36 children with suspected MIS HGNC ( MIS HGNC group). Prevalence, antigen specificity and neutralizing capability of SARS-CoV-2 antibodies were tested. Antibody frequency and titres against Nucleocapsid (N PROTEIN) and Spike (S) of the four seasonal coronaviruses (NL63, HKU1, 229E, OC43) were measured in a subset of seropositive patients (54 SARS-CoV-2 (HOS-P subgroup) and 15 MIS HGNC (MIS-P subgroup)), and in 118 matched SARS-CoV-2 seronegative patients (CTL subgroup). Findings: SARS-CoV-2 mean prevalence rate in HOSP children was 11.7% from April 1 to June 1. Neutralizing antibodies were found in 55.6% of seropositive children, and their relative frequency increased with time (up to 100 % by mid-May). A majority of MIS HGNC children (25/36) were SARS-CoV-2 seropositive, of which all tested (n=15) had neutralizing antibodies. On average, seropositive MIS HGNC children had higher N and S1 SARS-CoV-2 titres as compared to HOS children. Patients from HOS-P, MIS HGNC-P, and CTL subgroups had a similar prevalence of antibodies against the four seasonal HCoVs (66.9 -100%). The level of anti-SARS-CoV-2 antibodies was not significantly different in children who had prior seasonal coronavirus infection MESHD. Interpretation: Prior infection with HCoVs does not prevent SARS-CoV-2 infection MESHD and related MIS HGNC in children. Children develop neutralizing antibodies after SARS-CoV-2 infection MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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