Etherington, R.E. (Rachel E.)

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    Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury
    (2023) Landecho, M.F. (Manuel F.); Weeratunga, P. (Praveen); Klenerman, P. (Paul); Issa, F. (Fadi); Etherington, R.E. (Rachel E.); Denney, L. (Laura); Roberts, I.S.D. (Ian S. D.); Hester, J. (Joanna); Villalba-Esparza, M. (María); Sansom, S.N. (Stephen N.); Melero, I. (Ignacio); Cerundolo, L. (Lucia); Ogg, G. (Graham); Cross, A.R. (Amy R.); Ho, L.P. (Ling-Pei); Andrea, C.E. (Carlos Eduardo) de
    Severe lung damage resulting from COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways, and genes present across the spectrum of histopathological damage in COVID-19-affected lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from 46 areas of interest covering more than 62,000 cells within well-preserved lung samples from 3 patients. Despite substantial interpatient heterogeneity, we discovered evidence for a common immune-cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines, including CXCL9, CXCL10, and CXCL11, which are known to promote the recruitment of CXCR3+ immune cells. The TNF superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) were consistently upregulated in the areas with severe tissue damage. We used published spatial and single-cell SARS-CoV-2 data sets to validate our findings in the lung tissue from additional cohorts of patients with COVID-19. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies.
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    Single cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs
    (2023) Clelland, C. (Colin); Whalley, J. (Justin); Sims, D. (David); Weeratunga, P. (Praveen); Bull, J. (Joshua); Sergeant, M. (Martin); Klenerman, P. (Paul); Monaco, C. (Claudia); Gamez, E.C. (Eddie C.); Issa, F. (Fadi); Antanaviciute, A. (Agne); Etherington, R.E. (Rachel E.); Denney, L. (Laura); Byrne, H.M. (Helen M.); McGowan, S. (Simon); Richards, D. (Duncan); Ahern, D.J. (David J.); Udalova, I.A. (Irina A.); Zurke, Y.X. (Yasemin Xiomara); Turner, G.D.H. (Gareth D.H.); Melero, I. (Ignacio); Repapi, E. (Emmanouela); Ogg, G. (Graham); Cross, A.R. (Amy R.); Ho, L.P. (Ling-Pei); Andrea, C.E. (Carlos Eduardo) de; Taylor, S. (Stephen); Knight, J.C. (Julian C.); Vuppussetty, C. (Chaitanya); Dong, T. (Tao); Woo, J. (Jeongmin)
    Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis. Mathematical tools can be used to help identify pathological features from images of diseased lungs. Here, the authors used mathematical tools combined with high resolution multiplex imaging mass cytometry to show an association between immature neutrophils, CD8 T cells and proliferating alveolar epithelial cells in areas of maximal alveolar damage in COVID-19 lungs.