key: cord-0774601-qx0g4dbg authors: Jin, Kang; Bardes, Eric E.; Mitelpunkt, Alexis; Wang, Jake Y.; Bhatnagar, Surbhi; Sengupta, Soma; Krummel, Daniel Pomeranz; Rothenberg, Marc E.; Aronow, Bruce J. title: An Interactive Single Cell Web Portal Identifies Gene and Cell Networks in COVID-19 Host Responses date: 2021-09-10 journal: iScience DOI: 10.1016/j.isci.2021.103115 sha: 959f15f7e19b8ab280c3b456f18d0c9d427d3b8f doc_id: 774601 cord_uid: qx0g4dbg Numerous studies have provided single-cell transcriptome profiles of host responses to SARS-CoV-2 infection. Critically lacking however is a datamine that allows users to compare and explore cell profiles to gain insights and develop new hypotheses. To accomplish this, we harmonized datasets from COVID-19 and other control condition blood, bronchoalveolar lavage, and tissue samples, and derived a compendium of gene signature modules per cell type, subtype, clinical condition, and compartment. We demonstrate approaches to probe these via a new interactive web portal (http://toppcell.cchmc.org/). As examples, we develop three hypotheses: (1) a multicellular signaling cascade among alternatively differentiated monocyte-derived macrophages whose tasks include T cell recruitment and activation; (2) platelet subtypes with drastically modulated expression of genes responsible for adhesion, coagulation and thrombosis; and (3) a multilineage cell activator network able to drive extrafollicular B maturation via an ensemble of genes strongly associated with risk for developing post-viral autoimmunity. . 76 Additional sampling sites that could also be infected or affected have also been 77 approached in autopsy-derived materials from the central nervous system (Heming et anti-viral function ( Figure S5D ). Yet, the absence of cytokine and interferon response 214 pathways suggests the lack of mature immune responses ( Figure 3D) . Notably, 215 compared to mature neutrophils (Neu0 and Neu1) in the blood, the extravasated Table S3 ). However, the magnitude of activation and inflammatory responses in 238 TRAM3 is smaller than MoAM1,2,5. Not surprisingly, stronger antigen processing and 239 presentation activities were observed in TRAM3 relative to MoAM1,2,5 ( Figure 3D Table S3 ). Collectively, we concluded that tissue-resident macrophages were 241 greatly depleted in severe patients as the front-line innate immune responders in the 242 lung. Pro-inflammatory monocyte-derived macrophages infiltrate into the lung, leading 243 to the cytokine storm and damage of the lung. Large amounts of infiltration of MoAM 244 were not observed in mild COVID-19 patients, probably due to the controlled infection, 245 which could explain milder lung damages in those patients. Table S5 ). In addition, non-dividing plasmablasts showed unique isotypes 355 of immunoglobulin (Ig) in sub-regions of UMAP, whereas developing plasmablasts 356 displayed obscure Ig types (Figure S14E and S14F). Antibody production activities 357 were upregulated in non-dividing plasmablasts based on gene enrichment analysis 358 ( Figure S15A ; Table S5 ). Collectively, we inferred that non-dividing plasmablasts had 359 definite immunoglobulin isotypes and were actively involved in immune responses 360 towards COVID infection, while developing plasmablasts were less mature but highly 361 proliferative to replenish the repertoire of plasma cells. Collectively, using the COVID-19 single cell atlas data exploration environment, we 549 have illustrated is that researchers are now enabled to systematically explore, learn, 550 and formulate new hypotheses within and between compartments, cell types, and 551 biological processes, and provided access to these reprocessed datasets through a 552 suite of explorative and evaluative tools. Moreover, we have shown different hypotheses 553 can be developed and explored using the approaches that we have outlined and the 554 database that we have provided. Certainly additional critical information will also be 555 obtained using approaches that include in situ spatial, temporal data as well as those of 556 viral products and viral and inflammatory-process affected complexes. Next steps for 557 improving its ability to be mined more deeply will be based on additional statistical 558 methods that extend the current ToppCell / ToppGene Suite based on fuzzy measure 559 similarity, Page-Rank, and cell-cell signaling approaches. Figure S18 and Table S7 . , MSLN for AT1 cells; SFTPC, SFTPB for AT2 cells; SCGB3A2, SCGB1A1 for 868 Club cells; TPPP3, FOXJ1 for Ciliated cells; KRT5 for Basal cells; CFTR for Ionocytes; 869 FABP4, CD68 for tissue-resident macrophages; FCN1 for monocyte-derived 870 macrophages, TPSB2 for Mast cells. More details can be found in Table S2 . CD151 MYL9 ITGA2B F13A1 GP9 TGFB1 FERMT3 TLN1 PF4 CD9 FHL1 CXCL5 LIMS1 CLDN5 NCK2 LMNA DMTN PDGFA MYLK TBXA2R ALOX12 F2RL3 RGS18 PDLIM1 RAB4A TFPI GP1BA PDCD10 SERPINE1 PDGFB SERPINE2 ANK1 PTGS1 ITGB3 THBS1 PROS1 ANO6 JAM3 SELP CD68 SNCA FCER1G Vascular Disease and Thrombosis in 1020 SARS-CoV-2-Infected Rhesus Macaques The immune cell landscape in 1023 kidneys of patients with lupus nephritis Systems biological 1026 assessment of immunity to mild versus severe COVID-19 infection in humans The role of CXCR5 and its ligand CXCL13 in the 1030 compartmentalization of lymphocytes in thyroids affected by autoimmune thyroid 1031 diseases Targeting potential drivers of COVID-19: Neutrophil extracellular traps Lung 1038 transplantation for patients with severe COVID-19 Imbalanced Host Response 1041 to SARS-CoV-2 Drives Development of COVID-19 EnhancedVolcano: Publication-ready volcano plots 1043 with enhanced colouring and labeling COVID-19: immunopathology and its implications for therapy ToppGene Suite for gene 1049 list enrichment analysis and candidate gene prioritization COVID-19 severity correlates with 1053 airway epithelium-immune cell interactions identified by single-cell analysis Expansion of plasmablasts 1057 and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia COVID-1061 19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets Systematic 1068 comparison of single-cell and single-nucleus RNA-sequencing methods Role 1071 of endothelial heparanase in delayed-type hypersensitivity Covid-19 and 1074 autoimmunity Overlapping B cell pathways in severe COVID-1076 19 and lupus High levels of anti-SSA/Ro antibodies in COVID-1079 19 patients with severe respiratory failure: a case-based review A mechanistic model and 1083 therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm Elife 9 Soluble heparan sulfate 1086 fragments generated by heparanase trigger the release of pro-inflammatory cytokines 1087 through TLR-4 Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia Mapping Systemic Inflammation 1094 and Antibody Responses in Multisystem Inflammatory Syndrome in Children Single-cell analysis of two severe COVID-19 patients reveals a monocyte-1098 associated and tocilizumab-responding cytokine storm Impaired type I interferon 1101 activity and inflammatory responses in severe COVID-19 patients Integrated analysis of multimodal 1105 single-cell data The clinical course and its correlated immune status in COVID-1108 19 pneumonia Platelet-based coagulation: 1110 different populations, different functions Neurological Manifestations 1114 of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in 1115 Cerebrospinal Fluid Preferential recruitment 1118 of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and 1119 its animal model The unique characteristics of COVID-19 coagulopathy The coagulopathy, endotheliopathy, and 1123 vasculitis of COVID-19 Heparanase and the hallmarks of cancer Inference and analysis of cell-cell communication 1128 using CellChat ToppCluster: a multiple gene list feature analyzer for comparative enrichment clustering 1131 and network-based dissection of biological systems CXCL13 antibody for the treatment 1135 of autoimmune disorders CCR 7 Ligands Are Required for Development of 1138 Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent 1139 Author 1142 Correction: A dynamic COVID-19 immune signature includes associations with poor 1143 prognosis Serum BLC/CXCL13 concentrations and renal expression of CXCL13/CXCR5 in 1146 patients with systemic lupus erythematosus and lupus nephritis Immunophenotyping of COVID-19 and influenza 1150 highlights the role of type I interferons in development of severe COVID-19 Coagulation abnormalities and 1153 thrombosis in patients with COVID-19 Single-cell landscape of bronchoalveolar immune cells in patients with 1156 COVID-19 CD79a: a novel marker for B-cell 1159 neoplasms in routinely processed tissue samples The Role of 1161 Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage 1162 Activation Syndrome-Like Disease COVID-19: consider cytokine storm 1165 syndromes and immunosuppression Author Correction: Pathological inflammation in 1167 patients with COVID-19: a key role for monocytes and macrophages Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With 1176 Respiratory Failure and Coagulopathy Increased expression of heparanase in symptomatic carotid atherosclerosis SARS-CoV-2: a storm is raging Megakaryocytes and 1184 platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A 1185 case series An immune-cell 1188 signature of bacterial sepsis Autoinflammatory and autoimmune conditions at the crossroad of COVID-19 Integrated single 1195 cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination COVID-19 infection: the perspectives on immune 1206 responses Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19 Interplay between coagulation and 1212 vascular inflammation in sickle cell disease Upregulation of CCR4 in activated 1215 CD8+ T cells indicates enhanced lung homing in patients with severe acute SARS-CoV-1216 2 infection Analysis and classification of B-cell infiltrates in lupus 1219 and ANCA-associated nephritis Comprehensive Integration of 1222 Single-Cell Data Integrating platelet and coagulation activation in fibrin clot formation The trinity of 1227 COVID-19: immunity, inflammation and intervention Hematological findings and complications of COVID-19 Extracellular Traps: Villains and Targets in Arterial, Venous, and Cancer Characteristics of Peripheral Lymphocyte Subset Alteration in 1236 COVID-19 Pneumonia A single-cell atlas of 1239 the peripheral immune response in patients with severe COVID-19 Multi-omic profiling reveals widespread 1243 dysregulation of innate immunity and hematopoiesis in COVID-19 SCANPY: large-scale single-cell gene 1245 expression data analysis Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus 1248 erythematosus disease activity Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia Defining 1255 inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating 1256 single-cell transcriptomics and mass cytometry Cytokine storm and immunomodulatory therapy in COVID-19: Role of 1258 chloroquine and anti-IL-6 monoclonal antibodies Clinical and autoimmune characteristics of severe and critical 1261 cases of COVID-19 Neutrophil extracellular traps and 1264 thrombosis in COVID-19 IL20RB IL15RA CCR10 CCL25 IL10RB IL17RE OAS1 IFNAR2 IFNAR1 ISG15 IFI44 STAT1 IFI16 CCR2 IL17RC CD4 IL6R IL13RA1 IL18 IL1RL2 IL1A IL1B IL10 CCL2 IL31RA CCL20 CXCL3 CXCL2 IFIT3 IFIT1 CXCL9 IL17RA CCR1 IFNGR1 IFITM3 IL15 CSF1R CXCL16 IFNGR2 CXCL10 ACKR3 IL1R2 CSF2RB IL1RAP IL1R1 CXCL1 CCR3 CXCR2 CXCR1 IL18R1 IL3RA CXCR3 IL6 IL4R IL16 HLA-DQA2 HLA-DRB5 HLA-DQA1 HLA-DQB1 HLA-DMB HLA-DMA HLA-DRA HLA-DRB1 HLA-DPA1 HLA-DPB1 HLA-DOA IL7 HLA-DOB CXCR5 CCR6 IL5RA IL23R IL6ST IL11RA IL23A IL7R CCR7 IL2RA CCR4 IL24 CCL28 CXCR4 IL2RG CCR5 CCL23 IL21R IL27RA IL12RB1 IL10RA CXCR6 IL18RAP IL17C IL12RB2 IL2RB CCL18 IFNG CCL4 CCL5 CCL3 PF4V1 PF4 PPBP CXCL5 IL20RB IL15RA CCR10 CCL25 IL10RB IL17RE OAS1 IFNAR2 IFNAR1 ISG15 IFI44 STAT1 IFI16 CCR2 IL17RC CD4 IL6R IL13RA1 IL18 IL1RL2 IL1A IL1B IL10 CCL2 IL31RA CCL20 CXCL3 CXCL2 IFIT3 IFIT1 CXCL9 IL17RA CCR1 IFNGR1 IFITM3 IL15 CSF1R CXCL16 IFNGR2 CXCL10 ACKR3 IL1R2 CSF2RB IL1RAP IL1R1 CXCL1 CCR3 CXCR2 CXCR1 IL18R1 IL3RA CXCR3 IL6 IL4R IL16 HLA-DQA2 HLA-DRB5 HLA-DQA1 HLA-DQB1 HLA-DMB HLA-DMA HLA-DRA HLA-DRB1 HLA-DPA1 HLA-DPB1 HLA-DOA IL7 HLA-DOB CXCR5 CCR6 IL5RA IL23R IL6ST IL11RA IL23A IL7R CCR7 IL2RA CCR4 IL24 CCL28 CXCR4 IL2RG CCR5 CCL23 IL21R IL27RA IL12RB1 IL10RA CXCR6 IL18RAP IL17C IL12RB2 IL2RB CCL18 IFNG CCL4 CCL5 CCL3 PF4V1 PF4