LitCovid-sentences  

PMC:7252096 / 10135-21224 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T57 0-99 Sentence denotes Lung Epithelial Cell Expression of Host Factors Used by SARS-CoV-2 in Non-Human Primates and Humans
T58 100-304 Sentence denotes To investigate which cells within human and NHP tissues represent likely SARS-CoV-2 targets, we analyzed new and existing scRNA-seq datasets to assess which cell types express ACE2, alone or with TMPRSS2.
T59 305-650 Sentence denotes In a previously unpublished dataset consisting of NHP (Macaca mulatta) lung tissue collected after necropsy of healthy adult animals and analyzed by using Seq-Well v1 (Gierahn et al., 2017), we recovered at least 17 distinct major cell types, including various lymphoid, myeloid, and stromal populations (Figures 1 A–1C; Table S1; STAR Methods).
T60 651-823 Sentence denotes ACE2 and TMPRSS2 were primarily expressed in epithelial cells, with 6.7% of type II pneumocytes expressing ACE2 and 3.8% co-expressing ACE2 and TMPRSS2 (Figures 1B and 1C).
T61 824-1149 Sentence denotes Notably, the only double-positive cells observed were classified within the type II pneumocyte population; however, we also identified TMPRSS2 expression within club cells, ciliated epithelial cells, and type I pneumocytes, albeit at diminished abundance and frequency compared with type II pneumocytes (Figure 1C; Table S1).
T62 1150-1239 Sentence denotes Figure 1 Expression of ACE2 in Type II Pneumocytes in Healthy Lungs of Non-human Primates
T63 1240-1490 Sentence denotes (A) Schematic of protocol for isolation of lung tissue at necropsy from healthy non-human primates (M. mulatta, n = 3), creation of scRNA-seq libraries by using Seq-Well v1, and computational analysis to identify cell types by using unbiased methods.
T64 1491-1581 Sentence denotes UMAP projection of 3,793 single cells, points colored by cell identity (see STAR Methods).
T65 1582-1775 Sentence denotes (B) Uniform manifold approximation and projection (UMAP) as in (A), points colored by detection of ACE2 (coronavirus receptor, top) or TMPRSS2 (coronavirus S protein priming for entry, bottom).
T66 1776-1844 Sentence denotes Color coding is as follows: black, RNA positive; blue, RNA negative.
T67 1845-1961 Sentence denotes (C) Dot plot of 2 defining genes for each cell type (Table S1) (Bonferroni-adjusted p < 0.001) and ACE2 and TMPRSS2.
T68 1962-2153 Sentence denotes Dot size represents fraction of cells within that type expressing a given gene, and color intensity represents binned count-based expression amount (log(scaled UMI+1)) among expressing cells.
T69 2154-2315 Sentence denotes ACE2 is enriched in type II pneumocytes (6.7% expressing, Bonferroni-adjusted p = 8.62E−33), as is TMPRSS2 (29.5% expressing, Bonferroni-adjusted p = 8.73E−153).
T70 2316-2388 Sentence denotes Of all type II pneumocytes, 3.8% co-express ACE2 and TMPRSS2 (Table S9).
T71 2389-2466 Sentence denotes Red arrow indicates cell type with largest proportion of ACE2+TMPRSS2+ cells.
T72 2467-2662 Sentence denotes (D) Genes differentially expressed among ACE2+ and ACE2− type II pneumocytes. (SCDE package, FDR-adjusted p < 0.05 for IFNGR2, NT5DC1, ARL6IP1, and TRIM27; full results can be found in Table S1).
T73 2663-2681 Sentence denotes See also Table S1.
T74 2682-2893 Sentence denotes Next, we compared ACE2 + with ACE2 − type II pneumocytes to explore broader gene programs that differentiate putative SARS-CoV-2 target cells from cells of a similar phenotype and ontogeny (Figure 1D; Table S1).
T75 2894-3059 Sentence denotes Among genes significantly upregulated in ACE2 + type II pneumocytes, we observed IFNGR2 (false discovery rate [FDR]-adjusted p = 0.022), a receptor for type II IFNs.
T76 3060-3265 Sentence denotes Notably, previous work has demonstrated limited anti-viral potency of IFN-γ for SARS-associated coronaviruses, compared with that of type I IFNs, at least in vitro (Sainz et al., 2004, Zheng et al., 2004).
T77 3266-3584 Sentence denotes Other co-regulated genes of potential interest include TRIM27 (FDR-adjusted p = 0.025), as well as NT5DC1 (FDR-adjusted p = 0.003) and ARL6IP1 (FDR-adjusted p = 0.047), which were upregulated in the A549 adenocarcinoma alveolar basal epithelial cell line after exposure to IFN-α and IFN-γ for 6 h (Sanda et al., 2006).
T78 3585-3850 Sentence denotes We found IFNAR1 consistently expressed among both ACE2 + type II pneumocytes and ACE2 + TMPRSS2 + co-expressing type II pneumocytes, but its level of upregulation compared with all remaining pneumocytes did not meet statistical significance (FDR-adjusted p = 0.11).
T79 3851-4021 Sentence denotes This analysis finds ACE2 + cells enriched within a rare fraction of secretory cells in NHPs and that ACE2 expression is co-regulated with genes involved in IFN responses.
T80 4022-4268 Sentence denotes To assess whether the findings from NHP lung cells were similarly present in humans, we analyzed a previously unpublished scRNA-seq dataset derived from surgical resections of fibrotic lung tissue collected with Seq-Well S3 (Hughes et al., 2019).
T81 4269-4465 Sentence denotes Unsupervised analysis identified multiple cell types and subtypes of immune cells (Figures 2 A–2C; STAR Methods), as defined by the genes displayed in Figure 2C (full lists available in Table S2).
T82 4466-4649 Sentence denotes Here, we found that ACE2 and TMPRSS2 were primarily expressed within type II pneumocytes and ciliated cells, in line with our analysis of the NHP-derived cells (Figures 1 and 2A, 2B).
T83 4650-4904 Sentence denotes In type II pneumocytes (identified by unique expression of surfactant proteins SFTPC, SFTPB, and SFTPA1), we found 1.4% of cells expressing ACE2 (FDR-adjusted p = 1.35E−21), 34.2% expressing TMPRSS2 (FDR-adjusted p < 1E−300), and 0.8% co-expressing both.
T84 4905-5050 Sentence denotes In ciliated cells, we found 7% were ACE2 + (FDR-adjusted p = 5E−64), 24.6% were TMPRSS2 + (FDR-adjusted p = 3.8E−30), and 5.3% co-expressed both.
T85 5051-5199 Sentence denotes Figure 2 Select Lung Epithelial Cells from Control, HIV-1-Infected, and Mycobacterium-tuberculosis-Infected Human Donors Co-Express ACE2 and TMPRSS2
T86 5200-5413 Sentence denotes (A) Schematic of protocol for isolation of human lung tissue from surgical excess, creation of scRNA-seq libraries by using Seq-Well S3, and computational analysis to identify cell types by using unbiased methods.
T87 5414-5542 Sentence denotes Shown on the right is a UMAP projection of 18,915 cells across 8 donors (n = 3 TB+HIV+; n = 3 TB+; n = 2 non-infected patients).
T88 5543-5622 Sentence denotes Cells represented by points, colored according to cell type (see STAR Methods).
T89 5623-5716 Sentence denotes (B) UMAP projection as in (A), points colored by detection of ACE2 (top) or TMPRSS2 (bottom).
T90 5717-5785 Sentence denotes Color coding is as follows: black, RNA positive; blue, RNA negative.
T91 5786-6077 Sentence denotes (C) Dot plot of 2 defining genes for each cell type (FDR-adjusted p < 0.001), and ACE2 and TMPRSS2; dot size represents fraction of cells within cell type expressing a given gene, and color intensity represents binned count-based expression amount (log(scaled UMI+1)) among expressing cells.
T92 6078-6130 Sentence denotes All cluster-defining genes are provided in Table S2.
T93 6131-6209 Sentence denotes Red arrow indicates cell types with largest proportion of ACE2+TMPRSS2+ cells.
T94 6210-6340 Sentence denotes (D) Volcano plot identifying significantly upregulated genes in ACE2+TMPRSS2+ pneumocytes compared with all remaining pneumocytes.
T95 6341-6425 Sentence denotes Red points represent genes with a FDR-adjusted p < 0.05, and log2(fold change) >1.5.
T96 6426-6499 Sentence denotes Text highlighting specific genes; the full list is available in Table S2.
T97 6500-6601 Sentence denotes (E) Expression of ACE2 across human donors by HIV and TB status (p = 0.009 by likelihood-ratio test).
T98 6602-6620 Sentence denotes See also Table S2.
T99 6621-6887 Sentence denotes As above, to assess for cellular pathways significantly co-expressed within putative target cells for SARS-CoV-2, we computed differentially expressed genes between ACE2 + TMPRSS2 + type II pneumocytes and all other type II pneumocytes (Figures 2C and 2D; Table S2).
T100 6888-7091 Sentence denotes We found significant enrichment of BATF among ACE2 + TMPRSS2 + cells (FDR-adjusted p = 3.25E−7), which has been demonstrated previously to be upregulated by type I and type II IFNs (Murphy et al., 2013).
T101 7092-7336 Sentence denotes Of note, we also observed TRIM28 co-expressed with ACE2 and TMPRSS2 among type II pneumocytes in this dataset (FDR-adjusted p = 2.34E−9), which might play a role in potentiating an IFN response in lung epithelial cells (Krischuns et al., 2018).
T102 7337-7549 Sentence denotes Within this cohort of donors, 3 individuals were human immunodeficiency virus (HIV)+ and diagnosed with active tuberculosis, 3 donors had active tuberculosis and were HIV−, and 2 were negative for both pathogens.
T103 7550-7818 Sentence denotes Surprisingly, we found that all of the ACE2 + cells across all cell types were derived from HIV+ Mycobacterium tuberculosis (Mtb)+ donors despite approximately equivalent recovery of epithelial cell types from all donors (likelihood-ratio test, p = 0.009) (Figure 2E).
T104 7819-8361 Sentence denotes Given limited cell and patient numbers combined with potential sampling biases, we caution that this observation requires much broader cohorts to validate a potential role for co-infections; still, we note our observation is suggestive of a role for chronic IFNs in the induction of ACE2, given that HIV infection is associated with persistent upregulation of ISGs, and we observed elevated amounts of IFNAR2, IFI30, and IKBKB (Utay and Douek, 2016) (FDR-adjusted p = 1.1E−6, 8.8E−9, 1.57E−7, respectively; HIV+ versus HIV− epithelial cells).
T105 8362-8659 Sentence denotes Next, using a previously unpublished scRNA-seq dataset consisting of granuloma and adjacent, uninvolved lung samples from Mtb-infected NHPs (Macaca fascicularis) collected with Seq-Well S3, we identified subsets of epithelial cells expressing ACE2 and TMPRSS2 (Figure S1 ; Table S3; STAR Methods).
T106 8660-8929 Sentence denotes The majority of ACE2 + TMPRSS2 + cells were, once again, type II pneumocytes (22%) and type I pneumocytes (9.7%) and were largely enriched within granulomatous regions compared with those in adjacent uninvolved lung (Figures S1B and S1C) (p = 0.006, Fisher Exact Test).
T107 8930-9103 Sentence denotes ACE2 + TMPRSS2 + type II pneumocytes expressed significantly higher amounts of antimicrobial effectors such as LCN2 compared with remaining type II pneumocytes (Figure S1D).
T108 9104-9373 Sentence denotes Cells with club cell/secretory, type I pneumocyte, and ciliated cell types also contained some ACE2 + TMPRSS2 + cells, but we did not have sufficient power to detect significantly differentially expressed genes between these cells and other cells within those clusters.
T109 9374-9590 Sentence denotes Altogether, we identify ACE2 + TMPRSS2 + cells in lower airways of humans and NHPs with consistent cellular phenotypes and evidence supporting a potential role for IFN-associated inflammation in upregulation of ACE2.
T110 9591-9673 Sentence denotes Figure S1 NHP Tuberculosis Infected Lung and Granuloma, Related to Figures 1 and 2
T111 9674-9678 Sentence denotes (A).
T112 9679-9810 Sentence denotes UMAP projection of epithelial cells (1,099 cells) colored by annotated cell type, tissue source, and gating as ACE2+TMPRSS2+ cells.
T113 9811-9934 Sentence denotes ACE2+TMPRSS2+ cells comprise 11% of ciliated cells, 16% of club cells, 10% type I pneumocytes, and 22% type II pneumocytes.
T114 9935-9979 Sentence denotes Data generated using Seq-Well S3 (Table S3).
T115 9980-9984 Sentence denotes (B).
T116 9985-10108 Sentence denotes Number of cells (left) and % (right) ACE2+TMPRSS2+ cells by tissue source (granuloma versus uninvolved lung) and cell type.
T117 10109-10264 Sentence denotes Ciliated cells and club cells were omitted from this analysis as we detected too few cells (< 7 total cells) belonging to these clusters in the granulomas.
T118 10265-10331 Sentence denotes Statistical significance assessed by Fisher Exact Test (Table S3).
T119 10332-10336 Sentence denotes (C).
T120 10337-10427 Sentence denotes Dot plot of top cluster defining genes for each epithelial cell type and ACE2 and TMPRSS2.
T121 10428-10602 Sentence denotes Dot size represents fraction of cells expressing, and color intensity represents average log(normalized UMI + 1) among all cells in each group scaled between 0 and 1 by gene.
T122 10603-10756 Sentence denotes ACE2 expression is enriched in club cells (Bimodal test, Bonferroni-corrected p < 0.001), ciliated cells (p < 0.005), and type I pneumocytes (p < 0.001).
T123 10757-10864 Sentence denotes TMPRSS2 expression is enriched in type I pneumocytes (p < 0.001) and ciliated cells (p < 0.001) (Table S3).
T124 10865-10869 Sentence denotes (D).
T125 10870-11089 Sentence denotes Dot plot of genes differentially expressed between ACE2+TMPRSS2+ epithelial cells versus rest (Bimodal test, Bonferroni-corrected p < 0.01, log fold change > 0.5). (Table S3, c = number of cells, n = number of animals).