Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells
Mark Lee,Mark Lee,Chun Ye,Alexandra-Chloé Villani,Alexandra-Chloé Villani,Towfique Raj,Towfique Raj,Towfique Raj,Weibo Li,Weibo Li,Thomas Eisenhaure,Thomas Eisenhaure,Selina Imboywa,Portia Chipendo,F. Ann Ran,Kamil Slowikowski,Lucas D. Ward,Khadir Raddassi,Cristin McCabe,Cristin McCabe,Michelle Lee,Irene Y. Frohlich,David A. Hafler,Manolis Kellis,Soumya Raychaudhuri,Feng Zhang,Feng Zhang,Barbara E. Stranger,Christophe Benoist,Philip L. De Jager,Philip L. De Jager,Philip L. De Jager,Aviv Regev,Aviv Regev,Nir Hacohen,Nir Hacohen +35 more
TLDR
In this paper, the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells were investigated using a set of 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-β (IFN-β).Abstract:
Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-β (IFN-β). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.read more
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A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.
David E. Gordon,Gwendolyn M. Jang,Mehdi Bouhaddou,Jiewei Xu,Kirsten Obernier,Kris M. White,Matthew J. O’Meara,Veronica V. Rezelj,Jeffrey Z. Guo,Danielle L. Swaney,Tia A. Tummino,Ruth Hüttenhain,Robyn M. Kaake,Alicia L. Richards,Beril Tutuncuoglu,Helene Foussard,Jyoti Batra,Kelsey M. Haas,Maya Modak,Minkyu Kim,Paige Haas,Benjamin J. Polacco,Hannes Braberg,Jacqueline M. Fabius,Manon Eckhardt,Margaret Soucheray,Melanie J. Bennett,Merve Cakir,Michael McGregor,Qiongyu Li,Bjoern Meyer,Ferdinand Roesch,Thomas Vallet,Alice Mac Kain,Lisa Miorin,Elena Moreno,Zun Zar Chi Naing,Yuan Zhou,Shiming Peng,Ying Shi,Ziyang Zhang,Wenqi Shen,Ilsa T Kirby,James E. Melnyk,John S. Chorba,Kevin Lou,Shizhong Dai,Inigo Barrio-Hernandez,Danish Memon,Claudia Hernandez-Armenta,Jiankun Lyu,Christopher J.P. Mathy,Tina Perica,Kala Bharath Pilla,Sai J. Ganesan,Daniel J. Saltzberg,Rakesh Ramachandran,Xi Liu,Sara Brin Rosenthal,Lorenzo Calviello,Srivats Venkataramanan,Jose Liboy-Lugo,Yizhu Lin,Xi Ping Huang,Yongfeng Liu,Stephanie A. Wankowicz,Markus Bohn,Maliheh Safari,Fatima S. Ugur,Cassandra Koh,Nastaran Sadat Savar,Quang Dinh Tran,Djoshkun Shengjuler,Sabrina J. Fletcher,Michael C. O’Neal,Yiming Cai,Jason C.J. Chang,David J. Broadhurst,Saker Klippsten,Phillip P. Sharp,Nicole A. Wenzell,Duygu Kuzuoğlu-Öztürk,Hao-Yuan Wang,Raphael Trenker,Janet M. Young,Devin A. Cavero,Devin A. Cavero,Joseph Hiatt,Joseph Hiatt,Theodore L. Roth,Ujjwal Rathore,Ujjwal Rathore,Advait Subramanian,Julia Noack,Mathieu Hubert,Robert M. Stroud,Alan D. Frankel,Oren S. Rosenberg,Kliment A. Verba,David A. Agard,Melanie Ott,Michael Emerman,Natalia Jura,Mark von Zastrow,Eric Verdin,Eric Verdin,Alan Ashworth,Olivier Schwartz,Christophe d'Enfert,Shaeri Mukherjee,Matthew P. Jacobson,Harmit S. Malik,Danica Galonić Fujimori,Trey Ideker,Charles S. Craik,Stephen N. Floor,James S. Fraser,John D. Gross,Andrej Sali,Bryan L. Roth,Davide Ruggero,Jack Taunton,Tanja Kortemme,Pedro Beltrao,Marco Vignuzzi,Adolfo García-Sastre,Kevan M. Shokat,Brian K. Shoichet,Nevan J. Krogan +128 more
TL;DR: A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.
Journal ArticleDOI
Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors.
Alexandra-Chloé Villani,Alexandra-Chloé Villani,Rahul Satija,Rahul Satija,Gary Reynolds,Siranush Sarkizova,Karthik Shekhar,James Fletcher,Morgane Griesbeck,Andrew Butler,Shiwei Zheng,Suzan Lazo,Laura Jardine,David Dixon,Emily Stephenson,Emil Nilsson,Ida Grundberg,David McDonald,Andrew Filby,Weibo Li,Weibo Li,Philip L. De Jager,Philip L. De Jager,Orit Rozenblatt-Rosen,Andrew A. Lane,Andrew A. Lane,Muzlifah Haniffa,Muzlifah Haniffa,Aviv Regev,Aviv Regev,Aviv Regev,Nir Hacohen,Nir Hacohen +32 more
TL;DR: This refined analysis has identified, among others, a previously unknown dendritic cell population that potently activates T cells and reclassify pDCs as the originally described “natural interferon-producing cells (IPCs)” with weaker T cell proliferation induction ability.
Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors
Alexandra-Chloé Villani,Alexandra-Chloé Villani,Rahul Satija,Rahul Satija,Gary Reynolds,Siranush Sarkizova,Karthik Shekhar,James Fletcher,Morgane Griesbeck,Andrew Butler,Shiwei Zheng,Suzan Lazo,Laura Jardine,David Dixon,Emily Stephenson,Emil Nilsson,Ida Grundberg,David McDonald,Andrew Filby,Weibo Li,Weibo Li,Philip L. De Jager,Philip L. De Jager,Orit Rozenblatt-Rosen,Andrew A. Lane,Andrew A. Lane,Muzlifah Haniffa,Muzlifah Haniffa,Aviv Regev,Aviv Regev,Aviv Regev,Nir Hacohen,Nir Hacohen +32 more
TL;DR: In this paper, the authors performed single-cell RNA sequencing of ~2400 cells isolated from healthy blood donors and enriched for HLA-DR + lineage − cells, which led them to identify and validate six Dendritic cells (DCs) and four monocyte subtypes.
Journal ArticleDOI
The role of regulatory variation in complex traits and disease
Frank W. Albert,Leonid Kruglyak +1 more
TL;DR: Recent insights into the molecular nature of regulatory variants are reviewed and examples of complete chains of causality that link individual polymorphisms to changes in gene expression, which in turn result in physiological changes and, ultimately, disease risk are presented.
Journal ArticleDOI
Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity.
Melanie Schirmer,Melanie Schirmer,Sanne P. Smeekens,Hera Vlamakis,Martin Jaeger,Marije Oosting,Eric A. Franzosa,Eric A. Franzosa,Rob ter Horst,Trees Jansen,Liesbeth Jacobs,Marc Jan Bonder,Alexander Kurilshikov,Alexander Kurilshikov,Jingyuan Fu,Jingyuan Fu,Leo A. B. Joosten,Alexandra Zhernakova,Curtis Huttenhower,Curtis Huttenhower,Cisca Wijmenga,Mihai G. Netea,Ramnik J. Xavier +22 more
TL;DR: Validation of two predicted host-microbial interactions reveal that TNFα and IFNγ production are associated with specific microbial metabolic pathways: palmitoleic acid metabolism andtryptophan degradation to tryptophol.
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