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Artikel: Commensal myeloid crosstalk in neonatal skin regulates long-term cutaneous type 17 inflammation.

Dhariwala, Miqdad O / DeRogatis, Andrea M / Okoro, Joy N / Weckel, Antonin / Tran, Victoria M / Habrylo, Irek / Ojewumi, Oluwasunmisola T / Tammen, Allison E / Leech, John M / Merana, Geil R / Carale, Ricardo O / Barrere-Cain, Rio / Hiam-Galvez, Kamir J / Spitzer, Matthew H / Scharschmidt, Tiffany C

bioRxiv : the preprint server for biology

2023

Abstract: Early life microbe-immune interactions at barrier surfaces have lasting impacts on the trajectory towards health versus disease. Monocytes, macrophages and dendritic cells are primary sentinels in barrier tissues, yet the salient contributions of ... ...

Abstract	Early life microbe-immune interactions at barrier surfaces have lasting impacts on the trajectory towards health versus disease. Monocytes, macrophages and dendritic cells are primary sentinels in barrier tissues, yet the salient contributions of commensal-myeloid crosstalk during tissue development remain poorly understood. Here, we identify that commensal microbes facilitate accumulation of a population of monocytes in neonatal skin. Transient postnatal depletion of these monocytes resulted in heightened IL-17A production by skin T cells, which was particularly sustained among CD4
Sprache	Englisch
Erscheinungsdatum	2023-10-02
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2023.09.29.560039
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Long-term tolerance to skin commensals is established neonatally through a specialized dendritic cell subgroup.

Weckel, Antonin / Dhariwala, Miqdad O / Ly, Kevin / Tran, Victoria M / Ojewumi, Oluwasunmisola T / Riggs, Julianne B / Gonzalez, Jeanmarie R / Dwyer, Laura R / Okoro, Joy N / Leech, John M / Bacino, Margot S / Cho, Grace D / Merana, Geil / Anandasabapathy, Niroshana / Kumamoto, Yosuke / Scharschmidt, Tiffany C

Immunity

2023 Band 56, Heft 6, Seite(n) 1239–1254.e7

Abstract: Early-life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here, we showed that tolerance in skin was controlled by microbial interaction with a ... ...

Abstract	Early-life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here, we showed that tolerance in skin was controlled by microbial interaction with a specialized subset of antigen-presenting cells. More particularly, CD301b
Mesh-Begriff(e)	Animals ; Mice ; Humans ; Skin ; Dendritic Cells ; T-Lymphocytes, Regulatory ; Immune Tolerance ; Aldehyde Oxidoreductases/metabolism
Chemische Substanzen	RALDH2 protein, mouse (EC 1.2.1.36) ; Aldehyde Oxidoreductases (EC 1.2.-)
Sprache	Englisch
Erscheinungsdatum	2023-04-06
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2023.03.008
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: FLG Deficiency in Mice Alters the Early-Life CD4

Gonzalez, Jeanmarie R / Celli, Anna / Weckel, Antonin / Dhariwala, Miqdad O / Merana, Geil R / Ojewumi, Oluwasunmisola T / Okoro, Joy / Dwyer, Laura R / Tran, Victoria M / Meyer, Jason M / Mauro, Theodora M / Scharschmidt, Tiffany C

The Journal of investigative dermatology

2022 Band 143, Heft 5, Seite(n) 790–800.e12

Abstract: FLG variants underlie ichthyosis vulgaris and increased risk of atopic dermatitis, conditions typified by disruption of the skin microbiome and cutaneous immune response. Yet, it remains unclear whether neonatal skin barrier compromise because of FLG ... ...

Abstract	FLG variants underlie ichthyosis vulgaris and increased risk of atopic dermatitis, conditions typified by disruption of the skin microbiome and cutaneous immune response. Yet, it remains unclear whether neonatal skin barrier compromise because of FLG deficiency alters the quality of commensal-specific T cells and the functional impact of such responses. To address these questions, we profiled changes in the skin barrier and early cutaneous immune response of neonatal C57BL/6 Flg
Mesh-Begriff(e)	Animals ; Mice ; Bacteria ; CD4-Positive T-Lymphocytes ; Dermatitis, Atopic/genetics ; Intermediate Filament Proteins/genetics ; Mice, Inbred C57BL ; Skin
Chemische Substanzen	Intermediate Filament Proteins ; Fgfr1 protein, mouse (EC 2.7.10.1)
Sprache	Englisch
Erscheinungsdatum	2022-12-07
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2022.10.019
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A Deep Learning Approach to Antibiotic Discovery.

Cell

2020 Band 180, Heft 4, Seite(n) 688–702.e13

Abstract: Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting molecules with antibacterial activity. We performed ... ...

Abstract	Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub-halicin-that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules.
Mesh-Begriff(e)	Acinetobacter baumannii/drug effects ; Animals ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Cheminformatics/methods ; Clostridioides difficile/drug effects ; Databases, Chemical ; Drug Discovery/methods ; Machine Learning ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mycobacterium tuberculosis/drug effects ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Thiadiazoles/chemistry ; Thiadiazoles/pharmacology
Chemische Substanzen	Anti-Bacterial Agents ; SU 3327 ; Small Molecule Libraries ; Thiadiazoles
Sprache	Englisch
Erscheinungsdatum	2020-02-20
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2020.01.021
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A Deep Learning Approach to Antibiotic Discovery.

Cell

2020 Band 181, Heft 2, Seite(n) 475–483

Sprache	Englisch
Erscheinungsdatum	2020-04-16
Erscheinungsland	United States
Dokumenttyp	Published Erratum
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2020.04.001
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients.

Pita-Juarez, Yered / Karagkouni, Dimitra / Kalavros, Nikolaos / Melms, Johannes C / Niezen, Sebastian / Delorey, Toni M / Essene, Adam L / Brook, Olga R / Pant, Deepti / Skelton-Badlani, Disha / Naderi, Pourya / Huang, Pinzhu / Pan, Liuliu / Hether, Tyler / Andrews, Tallulah S / Ziegler, Carly G K / Reeves, Jason / Myloserdnyy, Andriy / Chen, Rachel /

Nam, Andy / Phelan, Stefan / Liang, Yan / Amin, Amit Dipak / Biermann, Jana / Hibshoosh, Hanina / Veregge, Molly / Kramer, Zachary / Jacobs, Christopher / Yalcin, Yusuf / Phillips, Devan / Slyper, Michal / Subramanian, Ayshwarya / Ashenberg, Orr / Bloom-Ackermann, Zohar / Tran, Victoria M / Gomez, James / Sturm, Alexander / Zhang, Shuting / Fleming, Stephen J / Warren, Sarah / Beechem, Joseph / Hung, Deborah / Babadi, Mehrtash / Padera, Robert F / MacParland, Sonya A / Bader, Gary D / Imad, Nasser / Solomon, Isaac H / Miller, Eric / Riedel, Stefan / Porter, Caroline B M / Villani, Alexandra-Chloé / Tsai, Linus T-Y / Hide, Winston / Szabo, Gyongyi / Hecht, Jonathan / Rozenblatt-Rosen, Orit / Shalek, Alex K / Izar, Benjamin / Regev, Aviv / Popov, Yury / Jiang, Z Gordon / Vlachos, Ioannis S

bioRxiv : the preprint server for biology

2022

Abstract: The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial ... ...

Abstract	The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. We identified hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells. Integrated analysis and comparisons with healthy controls revealed extensive changes in the cellular composition and expression states in COVID-19 liver, reflecting hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis. We also observed Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas, resembling similar responses in liver injury in mice and in sepsis, respectively. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition was dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.
Sprache	Englisch
Erscheinungsdatum	2022-10-28
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2022.10.27.514070
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients

Pita-Juarez, Yered / Karagkouni, Dimitra / Kalavros, Nikolaos / Melms, Johannes C. / Niezen, Sebastian / Delorey, Toni M. / Essene, Adam L / Brook, Olga R. / Pant, Deepti / Skelton-Badlani, Disha / Naderi, Pourya / Huang, Pinzhu / Pan, Liuliu / Hether, Tyler / Andrews, Tallulah S. / Ziegler, Carly G.K. / Reeves, Jason / Myloserdnyy, Andriy / Chen, Rachel /

Nam, Andy / Phelan, Stefan / Liang, Yan / Amin, Amit Dipak / Biermann, Jana / Hibshoosh, Hanina / Veregge, Molly / Kramer, Zachary / Jacobs, Christopher / Yalcin, Yusuf / Phillips, Devan / Slyper, Michal / Subramanian, Ayshwarya / Ashenberg, Orr / Bloom-Ackermann, Zohar / Tran, Victoria M. / Gomez, James / Sturm, Alexander / Zhang, Shuting / Fleming, Stephen J. / Warren, Sarah / Beechem, Joseph / Hung, Deborah / Babadi, Mehrtash / Padera, Robert F. / MacParland, Sonya A. / Bader, Gary D. / Imad, Nasser / Solomon, Isaac H. / Miller, Eric / Riedel, Stefan / Porter, Caroline B.M. / Villani, Alexandra-Chloé / Tsai, Linus T.-Y. / Hide, Winston / Szabo, Gyongyi / Hecht, Jonathan / Rozenblatt-Rosen, Orit / Shalek, Alex K. / Izar, Benjamin / Regev, Aviv / Popov, Yury / Jiang, Z. Gordon / Vlachos, Ioannis S.

bioRxiv

Abstract	The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. We identified hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells. Integrated analysis and comparisons with healthy controls revealed extensive changes in the cellular composition and expression states in COVID-19 liver, reflecting hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis. We also observed Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas, resembling similar responses in liver injury in mice and in sepsis, respectively. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition was dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2022-10-28
Verlag	Cold Spring Harbor Laboratory
Dokumenttyp	Artikel ; Online
DOI	10.1101/2022.10.27.514070
Datenquelle	COVID19

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Artikel: A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2.

Delorey, Toni M / Ziegler, Carly G K / Heimberg, Graham / Normand, Rachelly / Yang, Yiming / Segerstolpe, Asa / Abbondanza, Domenic / Fleming, Stephen J / Subramanian, Ayshwarya / Montoro, Daniel T / Jagadeesh, Karthik A / Dey, Kushal K / Sen, Pritha / Slyper, Michal / Pita-Juárez, Yered H / Phillips, Devan / Bloom-Ackerman, Zohar / Barkas, Nick / Ganna, Andrea /

Gomez, James / Normandin, Erica / Naderi, Pourya / Popov, Yury V / Raju, Siddharth S / Niezen, Sebastian / Tsai, Linus T-Y / Siddle, Katherine J / Sud, Malika / Tran, Victoria M / Vellarikkal, Shamsudheen K / Amir-Zilberstein, Liat / Atri, Deepak S / Beechem, Joseph / Brook, Olga R / Chen, Jonathan / Divakar, Prajan / Dorceus, Phylicia / Engreitz, Jesse M / Essene, Adam / Fitzgerald, Donna M / Fropf, Robin / Gazal, Steven / Gould, Joshua / Grzyb, John / Harvey, Tyler / Hecht, Jonathan / Hether, Tyler / Jane-Valbuena, Judit / Leney-Greene, Michael / Ma, Hui / McCabe, Cristin / McLoughlin, Daniel E / Miller, Eric M / Muus, Christoph / Niemi, Mari / Padera, Robert / Pan, Liuliu / Pant, Deepti / Pe'er, Carmel / Pfiffner-Borges, Jenna / Pinto, Christopher J / Plaisted, Jacob / Reeves, Jason / Ross, Marty / Rudy, Melissa / Rueckert, Erroll H / Siciliano, Michelle / Sturm, Alexander / Todres, Ellen / Waghray, Avinash / Warren, Sarah / Zhang, Shuting / Zollinger, Daniel R / Cosimi, Lisa / Gupta, Rajat M / Hacohen, Nir / Hide, Winston / Price, Alkes L / Rajagopal, Jayaraj / Tata, Purushothama Rao / Riedel, Stefan / Szabo, Gyongyi / Tickle, Timothy L / Hung, Deborah / Sabeti, Pardis C / Novak, Richard / Rogers, Robert / Ingber, Donald E / Jiang, Z Gordon / Juric, Dejan / Babadi, Mehrtash / Farhi, Samouil L / Stone, James R / Vlachos, Ioannis S / Solomon, Isaac H / Ashenberg, Orr / Porter, Caroline B M / Li, Bo / Shalek, Alex K / Villani, Alexandra-Chloé / Rozenblatt-Rosen, Orit / Regev, Aviv

bioRxiv : the preprint server for biology

2021

Abstract: The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and ... ...

Abstract	The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients' demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63
Sprache	Englisch
Erscheinungsdatum	2021-02-25
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2021.02.25.430130
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets.

Delorey, Toni M / Ziegler, Carly G K / Heimberg, Graham / Normand, Rachelly / Yang, Yiming / Segerstolpe, Åsa / Abbondanza, Domenic / Fleming, Stephen J / Subramanian, Ayshwarya / Montoro, Daniel T / Jagadeesh, Karthik A / Dey, Kushal K / Sen, Pritha / Slyper, Michal / Pita-Juárez, Yered H / Phillips, Devan / Biermann, Jana / Bloom-Ackermann, Zohar / Barkas, Nikolaos /

Ganna, Andrea / Gomez, James / Melms, Johannes C / Katsyv, Igor / Normandin, Erica / Naderi, Pourya / Popov, Yury V / Raju, Siddharth S / Niezen, Sebastian / Tsai, Linus T-Y / Siddle, Katherine J / Sud, Malika / Tran, Victoria M / Vellarikkal, Shamsudheen K / Wang, Yiping / Amir-Zilberstein, Liat / Atri, Deepak S / Beechem, Joseph / Brook, Olga R / Chen, Jonathan / Divakar, Prajan / Dorceus, Phylicia / Engreitz, Jesse M / Essene, Adam / Fitzgerald, Donna M / Fropf, Robin / Gazal, Steven / Gould, Joshua / Grzyb, John / Harvey, Tyler / Hecht, Jonathan / Hether, Tyler / Jané-Valbuena, Judit / Leney-Greene, Michael / Ma, Hui / McCabe, Cristin / McLoughlin, Daniel E / Miller, Eric M / Muus, Christoph / Niemi, Mari / Padera, Robert / Pan, Liuliu / Pant, Deepti / Pe'er, Carmel / Pfiffner-Borges, Jenna / Pinto, Christopher J / Plaisted, Jacob / Reeves, Jason / Ross, Marty / Rudy, Melissa / Rueckert, Erroll H / Siciliano, Michelle / Sturm, Alexander / Todres, Ellen / Waghray, Avinash / Warren, Sarah / Zhang, Shuting / Zollinger, Daniel R / Cosimi, Lisa / Gupta, Rajat M / Hacohen, Nir / Hibshoosh, Hanina / Hide, Winston / Price, Alkes L / Rajagopal, Jayaraj / Tata, Purushothama Rao / Riedel, Stefan / Szabo, Gyongyi / Tickle, Timothy L / Ellinor, Patrick T / Hung, Deborah / Sabeti, Pardis C / Novak, Richard / Rogers, Robert / Ingber, Donald E / Jiang, Z Gordon / Juric, Dejan / Babadi, Mehrtash / Farhi, Samouil L / Izar, Benjamin / Stone, James R / Vlachos, Ioannis S / Solomon, Isaac H / Ashenberg, Orr / Porter, Caroline B M / Li, Bo / Shalek, Alex K / Villani, Alexandra-Chloé / Rozenblatt-Rosen, Orit / Regev, Aviv

Nature

2021 Band 595, Heft 7865, Seite(n) 107–113

Abstract: COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ ... ...

Abstract	COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure
Mesh-Begriff(e)	Adult ; Aged ; Aged, 80 and over ; Atlases as Topic ; Autopsy ; Biological Specimen Banks ; COVID-19/genetics ; COVID-19/immunology ; COVID-19/pathology ; COVID-19/virology ; Endothelial Cells ; Epithelial Cells/pathology ; Epithelial Cells/virology ; Female ; Fibroblasts ; Genome-Wide Association Study ; Heart/virology ; Humans ; Inflammation/pathology ; Inflammation/virology ; Kidney/pathology ; Kidney/virology ; Liver/pathology ; Liver/virology ; Lung/pathology ; Lung/virology ; Male ; Middle Aged ; Myocardium/pathology ; Organ Specificity ; Phagocytes ; Pulmonary Alveoli/pathology ; Pulmonary Alveoli/virology ; RNA, Viral/analysis ; Regeneration ; SARS-CoV-2/immunology ; SARS-CoV-2/pathogenicity ; Single-Cell Analysis ; Viral Load
Chemische Substanzen	RNA, Viral
Sprache	Englisch
Erscheinungsdatum	2021-04-29
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-021-03570-8
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2

Delorey, Toni M. / Ziegler, Carly G. K. / Heimberg, Graham / Normand, Rachelly / Yang, Yiming / Segerstolpe, Asa / Abbondanza, Domenic / Fleming, Stephen J. / Subramanian, Ayshwarya / Montoro, Daniel T. / Jagadeesh, Karthik A. / Dey, Kushal / Sen, Pritha / Slyper, Michal / Pita-Juarez, Yered / Phillips, Devan / Bloom-Ackermann, Zohar / Barkas, Nick / Ganna, Andrea /

Gomez, James / Normandin, Erica / Naderi, Pourya / Popov, Yury V. / Raju, Siddharth S. / Niezen, Sebastian / Tsai, Linus T.-Y. / Siddle, Katherine J. / Sud, Malika / Tran, Victoria M. / Karuthedath Vellarikkal, Shamsudheen / Amir-Zilberstein, Liat / Atri, Deepak S. / Beechem, Joseph M / Brook, Olga R. / Chen, Jonathan / Divakar, Prajan / Dorceus, Phylicia / Engreitz, Jesse M / Essene, Adam / Fitzgerald, Donna M. / Fropf, Robin / Gazal, Steven / Gould, Joshua / Grzyb, John / Harvey, Tyler / Hecht, Jonathan / Hether, Tyler / Jane-Valbuena, Judit / Leney-Greene, Michael / Ma, Hui / McCabe, Cristin / McLoughlin, Daniel E. / Miller, Eric M. / Muus, Christoph / Niemi, Mari / Padera, Robert / Pan, Liuliu / Pant, Deepti / Pe'er, Carmel / Pfiffner-Borges, Jenna / Pinto, Christopher J. / Plaisted, Jacob / Reeves, Jason / Ross, Marty / Rudy, Melissa / Rueckert, Erroll H. / Siciliano, Michelle / Sturm, Alexander / Todres, Ellen / Waghray, Avinash / Warren, Sarah / Zhang, Shuting / Zollinger, Dan / Cosimi, Lisa / Gupta, Rajat M / Hacohen, Nir / Hide, Winston / Price, Alkes L. / Rajagopal, Jayaraj / Tata, Purushothama Rao / Riedel, Stefan / Szabo, Gyongyi / Tickle, Timothy L. / Hung, Deborah / Sabeti, Pardis C. / Novak, Richard / Rogers, Robert / Ingber, Donald E. / Jiang, Z Gordon / Juric, Dejan / Babadi, Mehrtash / Farhi, Samouil L. / Stone, James R. / Vlachos, Ioannis S. / Solomon, Isaac H. / Ashenberg, Orr / Porter, Caroline B.M. / Li, Bo / Shalek, Alex K. / Villani, Alexandra-Chloe / Rozenblatt-Rosen, Orit / Regev, Aviv

bioRxiv

Abstract	The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63+ intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profiles in situ and distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies.
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2021-02-25
Verlag	Cold Spring Harbor Laboratory
Dokumenttyp	Artikel ; Online
DOI	10.1101/2021.02.25.430130
Datenquelle	COVID19

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