DR41 DataRelease
Release Date: 10/15/2021
| SDY1743: Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 | ||||||||||
| Status: | New | |||||||||
| Description: | Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. The adaptive immune system responds to pathogens in an antigen-specific manner to develop protective immunity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects, and compared the response in unexposed controls | |||||||||
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| DOI: | 10.21430/M3LQIYECMJ | |||||||||
| Subjects: | 61 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1764: Distinct antibody responses to SARS-CoV-2 in children and adults | |||||||
| Status: | New | ||||||
| Description: | Clinical manifestations of COVID-19 caused by the new coronavirus SARS-CoV-2 are associated with age1. Adults develop respiratory symptoms, which can progress to acute respiratory distress syndrome (ARDS) in the most severe form, while children are largely spared from respiratory illness but can develop a life-threatening multisystem inflammatory syndrome (MIS-C). Here, we show distinct antibody responses in children and adults after SARS-CoV-2 infection. Adult COVID-19 cohorts had anti-spike (S) IgG, IgM and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibody, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. Moreover, children with and without MIS-C had reduced neutralizing activity as compared to both adult COVID-19 cohorts, indicating a reduced protective serological response. These results suggest a distinct infection course and immune response in children independent of whether they develop MIS-C, with implications for developing age-targeted strategies for testing and protecting the population. | ||||||
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| DOI: | 10.21430/M3060TKH6F | ||||||
| Subjects: | 89 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1765: Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases | |||||
| Status: | New | ||||
| Description: | Pro-inflammatory fibroblasts are critical to pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjogren's syndrome, and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited the understanding of which pathways are shared by multiple diseases. To investigate, we profiled patient-derived fibroblasts from inflamed and non-inflamed synovium, intestine, lung, and salivary glands with single-cell RNA-sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts were expanded in all inflamed tissues and additionally mapped to dermal analogues in a public atopic dermatitis atlas. We further confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. This work represents the first cross-tissue, single-cell fibroblast atlas revealing shared pathogenic activation states across four chronic inflammatory diseases. | ||||
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| DOI: | 10.21430/M3THY9WL9X | ||||
| Subjects: | 70 | ||||
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| Publications: | None | ||||
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| Clinical Assessments: | None | ||||
| SDY1767: Longitudinal profiling of respiratory and systemic immune responses in severe COVID-19 | |||||||
| Status: | New | ||||||
| Description: | Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract. | ||||||
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| DOI: | 10.21430/M3BZB4P8CI | ||||||
| Subjects: | 38 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1773: Human plasmacytoid dendritic cells mount a distinct antiviral response to virus-infected cells | |||||||
| Status: | New | ||||||
| Description: | Plasmacytoid dendritic cells (pDCs) can rapidly produce interferons and other soluble factors in response to extracellular viruses or virus mimics such as CpG-containing DNA. pDCs can also recognize live cells infected with certain RNA viruses, but the relevance and functional consequences of such recognition remain unclear. We studied the response of primary DCs to the prototypical persistent DNA virus, human cytomegalovirus (CMV). Human pDCs produced high amounts of type I interferon (IFN-I) when incubated with live CMV-infected fibroblasts but not with free CMV; the response involved integrin-mediated adhesion, transfer of DNA-containing virions to pDCs, and the recognition of DNA through TLR9. Compared with transient polyfunctional responses to CpG or free influenza virus, pDC response to CMV-infected cells was long-lasting, dominated by the production of IFN-I and IFN-III, and lacked diversification into functionally distinct populations. Similarly, pDC activation by influenza-infected lung epithelial cells was highly efficient, prolonged, and dominated by interferon production. Prolonged pDC activation by CMV-infected cells facilitated the activation of natural killer cells critical for CMV control. Last, patients with CMV viremia harbored phenotypically activated pDCs and increased circulating IFN-I and IFN-III. Thus, recognition of live infected cells is a mechanism of virus detection by pDCs that elicits a unique antiviral immune response. | ||||||
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| DOI: | 10.21430/M3LQG9JFFS | ||||||
| Subjects: | 81 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1774: Tumor Immune Microenvironment of mIDH1 and wtIDH1 Glioma GEMMs | |||||||
| Status: | New | ||||||
| Description: | Here, we examine the tumor immune microenvironment of GEMMs harboring wtIDH1 gliomas or mIDH1 gliomas. The results of these models are compared to identify differences in the immune cells, specifically the myeloid cell compartment. | ||||||
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| DOI: | 10.21430/M3QKW63FPO | ||||||
| Subjects: | 49 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1777: Th1 Polarization of JIA Synovial Fluid T Cells | |||||||||
| Status: | New | ||||||||
| Description: | Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children; yet, the cause of this disease remains unknown. We hoped that through disease pathway characterization, we could better understand immune responses in oligo JIA, and generate suggestions for means of controlling arthritic flares in oligo JIA. To do this we conducted detailed immunophenotyping of joint-infiltrating CD4+ T cells and the stability of Tregs in oligo JIA, which are found in the joints of affected patients. This was done with flow cytometry, bulk and single-cell RNA sequencing, DNA methylation studies, and Treg suppression assays. Within our study we enrolled 34 patients with oligo JIA, defined by ILAR criteria, who provided SF and peripheral blood (PB) samples. PB was also obtained from 8 pediatric and 9 adult controls. Flow cytometry was used to evaluate the T cell compartment in oligo JIA. Memory CD4, memory CD8, and gamma sigma T cells were enriched in oligo JIA joints. The frequencies of CD8+ memory T (Tmem) cells expressing the Th1 cytokine (IFNgamma) and chemokine receptor (CXCR3) in oligo JIA SF were assessed and compared to control PB. Similarly, the proportion of gamma sigma T lymphocytes expressing CXCR3 was compared between our two groups. We characterized CD4+ Tmem with additional flow cytometry studies. Paired PB and SF samples confirmed enrichment of CXCR3+ and IFNgamma+ CD4+ Tmem in oligo JIA joints. To assess for non-classical Th1 cells that jointly express Th1 and Th17 features, we evaluated the fraction of CD4+ T cells producing IFNgamma and IL-17. Because T cell stimulation alters expression of the Th17-associated chemokine receptor, CCR6; therefore, CD161 was used as an alternative marker of Th17 cells. To further understand gene expression in CD4+ T cells in oligo JIA, Tregs and Teffs from patients and controls were assessed with bulk RNA-sequencing (RNA-seq). Principal component analysis (PCA) of the transcriptomic data segregated samples by compartment (PB versus SF) and cell type (Teff versus Treg), even for patients receiving methotrexate. Gene set enrichment analysis (GSEA) was used to examine IFNgamma signaling gene sets in SF Tregs and SF Teffs compared to PB Tregs and PB Teffs. Gene sets related to antigen presentation, T cell receptor (TCR) signaling, and type I interferons were also examined in SF Tregs and SF Teffs. To assess for the possibility of cytokine-producing SF Tregs, indicating that these cells may have been reprogrammed to an effector population, we evaluated the transcriptomic signature of Tregs in oligo JIA. Treg-associated transcripts remained significantly elevated in SF Tregs compared to PB Tregs. To determine the stability and functionality of Th1-skewed (CXCR3+) SF Tregs, we used methylation studies and suppression assays. Because, Co-expression of Th1- and Th17-related genes and the robustness of the Treg transcriptomic signature in the sub-population of Tregs with Th1 features cannot be determined from bulk RNA-seq data. single-cell RNA sequencing (scRNA-seq) and TCR repertoire analysis on sorted Tregs and Teffs from the SF of 2 oligo JIA patients. Lastly, complete TCR data (paired CDR3? and CDR3? sequences) were recovered for a total of 5,509 cells (89% of the single-cell transcriptomic dataset). | ||||||||
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| DOI: | 10.21430/M3LNUWU2LK | ||||||||
| Subjects: | 53 | ||||||||
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| Clinical Assessments: | None | ||||||||
| SDY1799: Systemic Immunological Effects of Influvac Tetra Vaccination | |||||||
| Status: | New | ||||||
| Description: | Our observational studies have suggested that tetravalent influenza vaccination induces a wide reprogramming of the immune system and influences the susceptibility of future infections other than influenza. With a proteomics approach, among others, we aimed to identify possible mechanisms of this. | ||||||
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| DOI: | 10.21430/M3LIQ1CWAN | ||||||
| Subjects: | 10 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1844: Natural killer cell repertoire and function in HIV-1 persistence | |||||||
| Status: | New | ||||||
| Description: | Samples taken from people living with HIV-1 on long-term ART over the course of 50 weeks were profiled by CyTOF using antibody panels focused on natural killer cell receptors and ligands | ||||||
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| DOI: | 10.21430/M3RBU82MNR | ||||||
| Subjects: | 50 | ||||||
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| Publications: | None | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1868: Critical ACE2 Determinants of SARS-CoV-2 and Group 2B Coronavirus Infection and Replication | |||||||
| Status: | New | ||||||
| Description: | The angiotensin-converting enzyme 2 (ACE2) receptor is a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host range determinant, and understanding SARS-CoV-2-ACE2 interactions will provide important insights into COVID-19 pathogenesis and animal model development. SARS-CoV-2 cannot infect mice due to incompatibility between its receptor binding domain and the murine ACE2 receptor. Through molecular modeling and empirical in vitro validation, we identified 5 key amino acid differences between murine and human ACE2 that mediate SARS-CoV-2 infection, generating a chimeric humanized murine ACE2. Additionally, we examined the ability of the humanized murine ACE2 receptor to permit infection by an additional preemergent group 2B coronavirus, WIV-1, providing evidence for the potential pan-virus capabilities of this chimeric receptor. Finally, we predicted the ability of these determinants to inform host range identification of preemergent coronaviruses by evaluating hot spot contacts between SARS-CoV-2 and additional potential host receptors. Our results identify residue determinants that mediate coronavirus receptor usage and host range for application in SARS-CoV-2 and emerging coronavirus animal model development. | ||||||
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| DOI: | 10.21430/M3FE77I3XS | ||||||
| Subjects: | 0 | ||||||
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| SDY1869: Integrated modeling of metabolome, proteome, and immunome trajectories predicts labor onset | |||||||
| Status: | New | ||||||
| Description: | Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 ? 10-40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 ? 10-7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies | ||||||
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| DOI: | 10.21430/M3NZOJ19RM | ||||||
| Subjects: | 61 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1871: Maternal plasma miRNAs as potential biomarkers for detecting risk of SGA | ||||||||||
| Status: | New | |||||||||
| Description: | Small-for-gestational-age fetuses (SGA) (birthweight <10th centile) are at high risk for stillbirth or long-term adverse outcomes. Here, we investigate the ability of circulating maternal plasma miRNAs to determine the risk of SGA births. Maternal plasma samples from 29 women of whom 16 subsequently delivered normally grown babies and 13 delivered SGA (birthweight <5th centile) were selected from a total of 511 women recruited to form a discovery cohort in which expression data for a total of 800 miRNAs was determined using the Nanostring nCounter miRNA assay. Validation by RT-qPCR was performed in an independent cohort. Findings: Partial least-squares discriminant analysis (PLS-DA) of the Nanostring nCounter miRNA assay initially identified seven miRNAs at 12?14+6 weeks gestation, which discriminated between SGA cases and controls. Four of these were technically validated by RT-qPCR. Differential expression of two miRNA markers; hsa-miR-374a-5p (p = 0?0176) and hsa-let-7d-5p (p = 0?0036), were validated in an independent population of 95 women (SGA n = 12, Control n = 83). In the validation cohort, which was enriched for SGA cases, the ROC AUCs were 0?71 for hsa-miR-374a-5p, and 0?74 for hsa-let-7d-5p, and 0?77 for the two combined. Whilst larger population-wide studies are required to validate their performance, these findings highlight the potential of circulating miRNAs to act as biomarkers for early prediction of SGA births | |||||||||
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| DOI: | 10.21430/M3TU8P1DQ0 | |||||||||
| Subjects: | 29 | |||||||||
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| Clinical Assessments: | None | |||||||||
| SDY1872: Nitrate in Drinking Water during Pregnancy and sPTM | |||||||
| Status: | New | ||||||
| Description: | Nitrate is a widespread groundwater contaminant and a leading cause of drinking water quality violations in California. Associations between nitrate exposure and select adverse birth outcomes have been suggested, but few studies have examined gestational exposures to nitrate and risk of preterm birth (before 37 wk gestation). Objective: To investigate The association between elevated nitrate in drinking water and spontaneous preterm birth through a within-mother retrospective cohort study of births in California. Methods: Acquired over 6 million birth certificate records linked with Office of Statewide Health Planning and Development hospital discharge data for California births from 2000-2011. Used public water system monitoring records to estimate nitrate concentrations in drinking water for each woman's residence during gestation. Constructed a sample of 1,443,318 consecutive sibling births in order to conduct a within-mother analysis. Used separate conditional logistic regression models to estimate the odds of preterm birth at 20-31 and 32-36 wk, respectively, among women whose nitrate exposure changed between consecutive pregnancies. Results: Spontaneous preterm birth at 20?31 wk was increased in association with tap water nitrate concentrations during pregnancy of 5 to <10mg/L [odds ratio (OR)=1.47; 95% confidence interval (CI): 1.29, 1.67] and ?10mg/L (OR=2.52; 95% CI: 1.49, 4.26) compared with <5mg/L (as nitrogen). Corresponding estimates for spontaneous preterm birth at 32?36 wk were positive but close to the null for 5 to <10mg/L nitrate (OR=1.08; 95% CI: 1.02, 1.15) and for ?10mg/L nitrate (OR=1.05; 95% CI: 0.85, 1.31) vs. <5mg/L nitrate. Our findings were similar in several secondary and sensitivity analyses, including in a conventional individual-level design. Discussion: The results suggest that nitrate in drinking water is associated with increased odds of spontaneous preterm birth. Notably, we estimated modestly increased odds associated with tap water nitrate concentrations of 5 to <10mg/L (below the federal drinking water standard of 10mg/L) relative to <5mg/L. | ||||||
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| DOI: | 10.21430/M3A9W2XKY2 | ||||||
| Subjects: | 0 | ||||||
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| SDY1873: Lactobacillus-depleted vaginal microbiota in HIV-1 pregnant women are associated with increased local inflammation and PTM | |||||||
| Status: | New | ||||||
| Description: | Pregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. Methods: Prospective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored. Findings: There was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1?. Interpretation: There is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population | ||||||
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| DOI: | 10.21430/M3QNZXMTSJ | ||||||
| Subjects: | 0 | ||||||
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| SDY1876: Large-scale placenta DNA methylation mega-analysis on fetal sex | |||||||
| Status: | New | ||||||
| Description: | Although male-female differences in placental structure and function have been observed, little is understood about their molecular underpinnings. Here, we present a mega-analysis of 14 publicly available placenta DNA methylation (DNAm) microarray datasets to identify individual CpGs and regions associated with fetal sex. In the discovery dataset of placentas fromFull term pregnancies (N = 532 samples), 5,212 CpGs met genome-wide significance (p < 1E-8) and were enriched in pathways such as keratinization (FDR p-value = 7.37E-14), chemokine activity (FDR p-value = 1.56E-2), and eosinophil migration (FDR p-value = 1.83E-2). Nine DMRs were identified (fwerArea < 0.1) including a region in the promoter of ZNF300 that showed consistent differential DNAm in samples from earlier timepoints in pregnancy and appeared to be driven predominately by effects in the trophoblast cell type. We describe the largest study of fetal sex differences in placenta DNAm performed to date, revealing genes and pathways characterizing sex-specific placenta function and health outcomes later in life. | ||||||
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| DOI: | 10.21430/M3HD6FG5E9 | ||||||
| Subjects: | 0 | ||||||
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| Publications: | None | ||||||
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| SDY67: Bioinformatics Approach to 2010-2011 TIV Influenza A/H1N1 Vaccine Immune Profiling | |||||||||||||||||||||||||
| Status: | Updated | ||||||||||||||||||||||||
| Description: | Aim 1: Characterize Immune Profiles Over Time, Aim 2: Correlate Immune Profiles with Vaccine Immunogenicity,Aim 3: Replication of Immune Profiles and Verification of Models | ||||||||||||||||||||||||
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| DOI: | 10.21430/M3OYWCJHO1 | ||||||||||||||||||||||||
| Subjects: | 159 | ||||||||||||||||||||||||
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| Clinical Assessments: | None | ||||||||||||||||||||||||
| SDY997: AMP Lupus Network Project: Molecular Characterization of Lupus Nephritis and Correlation with Response to Therapy | |||||||||||
| Status: | Updated | ||||||||||
| Description: | Phase I will be devoted to the study of at least 45 subjects with lupus nephritis and 25 controls with the intent of achieving the following goals: (i) to assess feasibility of obtaining a sufficient yield of high quality data based on current and refined AMP SOPs, (ii) to assess recruitment rates and the number of sites necessary to effectively recruit for Phase II, (iii) to ensure that the technologies developed in Phase 0 are working well, especially with regard to transport and scaling up to handle specimens from multiple sites; (iv) to demonstrate that the selected technologies can be used for the purpose of reliably differentiating lupus nephritis kidneys from kidney tissue without lupus nephritis, (v) where necessary, to further refine the technologies before embarking on a large-scale project; and most importantly (vi) to provide critical data upon which to make rational decisions about key elements of the Phase II study design (e.g., eligibility criteria, estimates of variation for power calculations, and site-specific capability regarding patient recruitment, specimen handling, etc.). | ||||||||||
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| DOI: | 10.21430/M35FLWNXH1 | ||||||||||
| Subjects: | 118 | ||||||||||
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| SDY1352: INDIGO HLA and KIR part 1 | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | High resolution HLA and KIR typing in five CNS-related diseases. | |||||||||||||||
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| DOI: | 10.21430/M38ED12JYE | |||||||||||||||
| Subjects: | 9148 | |||||||||||||||
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| Publications: | None | |||||||||||||||
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