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11 results on '"Arjun Arkal, Rao"'

1. A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

Author

Jason A. Hackney, Haridha Shivram, Jason Vander Heiden, Chris Overall, Luz Orozco, Xia Gao, Eugene Kim, Nathan West, Aditi Qamra, Diana Chang, Arindam Chakrabarti, David F. Choy, Alexis J. Combes, Tristan Courau, Gabriela K. Fragiadakis, Arjun Arkal Rao, Arja Ray, Jessica Tsui, Kenneth Hu, Nicholas F. Kuhn, Matthew F. Krummel, David J. Erle, Kirsten Kangelaris, Aartik Sarma, Zoe Lyon, Carolyn S. Calfee, Prescott G. Woodruff, Rajani Ghale, Eran Mick, Ashley Byrne, Beth Shoshana Zha, Charles Langelier, Carolyn M. Hendrickson, Monique G.P. van der Wijst, George C. Hartoularos, Tianna Grant, Raymund Bueno, David S. Lee, John R. Greenland, Yang Sun, Richard Perez, Anton Ogorodnikov, Alyssa Ward, Chun Jimmie Ye, Thiru Ramalingam, Jacqueline M. McBride, Fang Cai, Anastasia Teterina, Min Bao, Larry Tsai, Ivan O. Rosas, Aviv Regev, Sharookh B. Kapadia, Rebecca N. Bauer, Carrie M. Rosenberger, Yumiko Abe-Jones, Michael Adkisson, K. Mark Ansel, Saurabh Asthana, Alexander Beagle, Sharvari Bhide, Cathy Cai, Saharai Caldera, Maria Calvo, Sidney A. Carrillo, Suzanna Chak, Stephanie Christenson, Zachary Collins, Spyros Darmanis, Angela Detweiler, Catherine DeVoe, Walter Eckalbar, Jeremy Giberson, Ana Gonzalez, Gracie Gordon, Paula Hayakawa Serpa, Alejandra Jauregui, Chayse Jones, Serena Ke, Divya Kushnoor, Tasha Lea, Deanna Lee, Aleksandra Leligdowicz, Yale Liu, Salman Mahboob, Lenka Maliskova, Michael Matthay, Elizabeth McCarthy, Priscila Muñoz-Sandoval, Norma Neff, Viet Nguyen, Nishita Nigam, Randy Parada, Maira Phelps, Logan Pierce, Priya Prasad, Sadeed Rashid, Gabriella Reeder, Nicklaus Rodriguez, Bushra Samad, Andrew Schroeder, Cole Shaw, Alan Shen, Austin Sigman, Pratik Sinha, Matthew Spitzer, Sara Sunshine, Kevin Tang, Luz Torres Altamirano, Alexandra Tsitsiklis, Erden Tumurbaatar, Vaibhav Upadhyay, Alexander Whatley, Andrew Willmore, Michael Wilson, Juliane Winkler, Kristine Wong, Kimberly Yee, Michelle Yu, Mingyue Zhou, and Wandi S. Zhu

Subjects
Clinical genetics, Molecular medicine, Immune response, Science
Abstract

Summary: Altered myeloid inflammation and lymphopenia are hallmarks of severe infections. We identified the upregulated EN-RAGE gene program in airway and blood myeloid cells from patients with acute lung injury from SARS-CoV-2 or other causes across 7 cohorts. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGEhi myeloid cells express features consistent with suppressor cell functionality, including low HLA-DR and high PD-L1. Sustained EN-RAGE program expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell dysfunction markers. IL-6 upregulated many EN-RAGE program genes in monocytes in vitro. IL-6 signaling blockade by tocilizumab in a placebo-controlled clinical trial led to rapid normalization of EN-RAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.

Published
2023
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2. Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

Author

Weiner, January, 3rd, Suwalski, Phillip, Holtgrewe, Manuel, Rakitko, Alexander, Thibeault, Charlotte, Müller, Melina, Patriki, Dimitri, Quedenau, Claudia, Krüger, Ulrike, Ilinsky, Valery, Popov, Iaroslav, Balnis, Joseph, Jaitovich, Ariel, Helbig, Elisa T, Lippert, Lena J, Stubbemann, Paula, Real, Luis M, Macías, Juan, Pineda, Juan A, Fernandez-Fuertes, Marta, Wang, Xiaomin, Karadeniz, Zehra, Saccomanno, Jacopo, Doehn, Jan-Moritz, Hübner, Ralf-Harto, Hinzmann, Bernd, Salvo, Mauricio, Blueher, Anja, Siemann, Sandra, Jurisic, Stjepan, Beer, Juerg H., Rutishauser, Jonas, Wiggli, Benedikt, Schmid, Hansruedi, Danninger, Kathrin, Binder, Ronald, Corman, Victor M, Mühlemann, Barbara, Arjun Arkal, Rao, Fragiadakis, Gabriela K., Mick, Eran, COMET, Consortium, Calfee, Carolyn S., Erle, David J., Hendrickson, Carolyn M., Kangelaris, Kirsten N., Krummel, Matthew F., Woodruff, Prescott G., Langelier, Charles R., Venkataramani, Urmila, García, Federico, Zyla, Joanna, Drosten, Christian, Alice, Braun, Jones, Terry C, Suttorp, Norbert, Witzenrath, Martin, Hippenstiel, Stefan, Zemojtel, Tomasz, Skurk, Carsten, Poller, Wolfgang, Borodina, Tatiana, Pa-COVID, Study Group, Ripke, Stephan, Sander, Leif E, Beule, Dieter, Landmesser, Ulf, Guettouche, Toumy, Kurth, Florian, and Heidecker, Bettina

Published
2021
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3. Bioinformatics Analysis of Publicly Available Single-Nuclei Transcriptomics Alzheimer’s Disease Datasets Reveals APOE Genotype-Specific Changes Across Cell Types in Two Brain Regions

Author

Stella A. Belonwu, Yaqiao Li, Daniel G. Bunis, Arjun Arkal Rao, Caroline Warly Solsberg, Tomiko Oskotsky, Alice L. Taubes, Brian Grone, Kelly A. Zalocusky, Gabriela K. Fragiadakis, Yadong Huang, and Marina Sirota

Subjects
Alzheimer’s disease, APOE, single-cell, RNA-sequencing, differential expression, network enrichment, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Alzheimer’s Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have revealed APOE genotype-specific transcriptomic differences; however, these differences have not been explored at a single-cell level. To elucidate more complex APOE genotype-specific disease-relevant changes masked by the bulk analysis, we leverage the first two single-nucleus RNA sequencing AD datasets from human brain samples, including nearly 55,000 cells from the prefrontal and entorhinal cortices. In each brain region, we performed a case versus control APOE genotype-stratified differential gene expression analysis and pathway network enrichment in astrocytes, microglia, neurons, oligodendrocytes, and oligodendrocyte progenitor cells. We observed more global transcriptomic changes in APOE4 positive AD cells and identified differences across APOE genotypes primarily in glial cell types. Our findings highlight the differential transcriptomic perturbations of APOE isoforms at a single-cell level in AD pathogenesis and have implications for precision medicine development in the diagnosis and treatment of AD.

Published
2022
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4. SARS-CoV-2 infection of airway organoids reveals conserved use of Tetraspanin-8 by Ancestral, Delta, and Omicron variants

Author

Lisiena Hysenaj, Samantha Little, Kayla Kulhanek, Melia Magnen, Kriti Bahl, Oghenekevwe M. Gbenedio, Morgan Prinz, Lauren Rodriguez, Christopher Andersen, Arjun Arkal Rao, Alan Shen, Jean-Christophe Lone, Leonard C. Lupin-Jimenez, Luke R. Bonser, Nina K. Serwas, Eran Mick, Mir M. Khalid, Taha Y. Taha, Renuka Kumar, Jack Z. Li, Vivianne W. Ding, Shotaro Matsumoto, Mazharul Maishan, Bharath Sreekumar, Camille Simoneau, Irina Nazarenko, Michael G. Tomlinson, Khajida Khan, Anne von Gottberg, Alex Sigal, Mark R. Looney, Gabriela K. Fragiadakis, David M. Jablons, Charles R. Langelier, Michael Matthay, Matthew Krummel, David J. Erle, Alexis J. Combes, Anita Sil, Melanie Ott, Johannes R. Kratz, and Jeroen P. Roose

Subjects
Tetraspanins, TSPAN8, Clinical Sciences, virus, Biochemistry, Vaccine Related, Clinical Research, Biodefense, Influenza A Virus, therapeutics, Genetics, Humans, 2.1 Biological and endogenous factors, H1N1 Subtype, Aetiology, Lung, Biobank, variants, SARS-CoV-2, Prevention, H1N1, COVID-19, single cell RNAseq, Pneumonia, Cell Biology, cell composition, Organoids, airway organoids, Emerging Infectious Diseases, Infectious Diseases, Good Health and Well Being, Influenzas, spectral flow, Pneumonia & Influenza, Biochemistry and Cell Biology, Infection, Developmental Biology
Abstract

Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with a spectrum of disease severity. The mechanistic explaining variations related to airway epithelium are relatively understudied. Here, we biobanked airway organoids (AO) by preserving stem cell function. We optimized viral infection with H1N1/PR8 and comprehensively characterized epithelial responses to SARS-CoV-2 infection in phenotypically stable AO from 20 different subjects. We discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection. TSPAN8 facilitates SARS-CoV-2 infection rates independently of ACE2-Spike interaction. In head-to-head comparisons with Ancestral SARS-CoV-2, Delta and Omicron VOC displayed lower overall infection rates of AO but triggered changes in epithelial response. All variants shared highest tropism for ciliated and goblet cells. TSPAN8-blocking antibodies diminish SARS-CoV-2 infection and may spur novel avenues for COVID-19 therapy.

Published
2023

5. Discovering Dominant Tumor Immune Archetypes in A Pan-Cancer Census

Author

Alexis J. Combes, Bushra Samad, Jessica Tsui, Nayvin W. Chew, Peter Yan, Gabriella C. Reeder, Divyashree Kushnoor, Alan Shen, Brittany Davidson, Andrea J. Barczak, Michael Adkisson, Austin Edwards, Mohammad Naser, Kevin C. Barry, Tristan Courau, Taymour Hammoudi, Rafael J. Argüello, Arjun Arkal Rao, Adam B. Olshen, Cathy Cai, Jenny Zhan, Katelyn C. Davis, Robin K. Kelley, Jocelyn S. Chapman, Chloe E. Atreya, Amar Patel, Adil I. Daud, Patrick Ha, Aaron A. Diaz, Johannes R. Kratz, Eric A. Collisson, Gabriela K. Fragiadakis, David J. Erle, Alexandre Boissonnas, Saurabh Asthana, Vincent Chan, Matthew F. Krummel, Matthew Spitzer, Lawrence Fong, Amanda Nelson, Raj Kumar, Justin Lee, Arun Burra, Joy Hsu, Caroline Hackett, Karen Tolentino, Jasmine Sjarif, Peter Johnson, Evans Shao, Darrell Abrau, Leonard Lupin, Cole Shaw, Zachary Collins, Tasha Lea, Carlos Corvera, Eric Nakakura, Julia Carnevale, Michael Alvarado, Kimberley Loo, Lawrence Chen, Melissa Chow, Jennifer Grandis, Will Ryan, Ivan El-Sayed, David Jablons, Gavitt Woodard, Maxwell W. Meng, Sima P. Porten, Hideho Okada, Margaret Tempero, Andrew Ko, Kim Kirkwood, Scott Vandenberg, Denise Guevarra, Erica Oropeza, Chris Cyr, Pat Glenn, Jennifer Bolen, Amanda Morton, Walter Eckalbar, University of California [San Francisco] (UC San Francisco), University of California (UC), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Biostatistics, University of California, San Francisco, and University of California (UC)-University of California (UC)

Subjects
Universities, Computational Biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Censuses, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Flow Cytometry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, Gene Expression Regulation, Neoplastic, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Neoplasms, Biomarkers, Tumor, Tumor Microenvironment, Cluster Analysis, Humans, San Francisco, RNA-Seq, Transcriptome, ComputingMilieux_MISCELLANEOUS
Abstract

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

Published
2021

6. Spatiotemporal co-dependency between macrophages and exhausted CD8

Author

Kelly, Kersten, Kenneth H, Hu, Alexis J, Combes, Bushra, Samad, Tory, Harwin, Arja, Ray, Arjun Arkal, Rao, En, Cai, Kyle, Marchuk, Jordan, Artichoker, Tristan, Courau, Quanming, Shi, Julia, Belk, Ansuman T, Satpathy, and Matthew F, Krummel

Subjects
Macrophages, Neoplasms, Tumor Microenvironment, Humans, Cell Differentiation, CD8-Positive T-Lymphocytes, Article
Abstract

T cell exhaustion is a major impediment to anti-tumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here we show that the biology of tumor-associated macrophages (TAM) and exhausted T cells (T(ex)) in the TME is extensively linked. We demonstrate that in vivo depletion of TAM reduces exhaustion programs in tumor-infiltrating CD8(+) T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that T(ex) express factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8(+) T cells engage in unique long-lasting antigen-specific synaptic interactions that fail to activate T cells but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor.

Published
2021

7. Bioinformatics Analysis of Publicly Available Single-Nuclei Transcriptomics Alzheimer's Disease Datasets Reveals

Author

Stella A, Belonwu, Yaqiao, Li, Daniel G, Bunis, Arjun Arkal, Rao, Caroline Warly, Solsberg, Tomiko, Oskotsky, Alice L, Taubes, Brian, Grone, Kelly A, Zalocusky, Gabriela K, Fragiadakis, Yadong, Huang, and Marina, Sirota

Abstract

Alzheimer's Disease (AD) is a complex neurodegenerative disease that gravely affects patients and imposes an immense burden on caregivers. Apolipoprotein E4 (APOE4) has been identified as the most common genetic risk factor for AD, yet the molecular mechanisms connecting APOE4 to AD are not well understood. Past transcriptomic analyses in AD have revealed

Published
2021

9. A Pan-Cancer Census of Dominant Tumor Immune Archetypes

Author

Alexis J. Combes, Bushra Samad, Jessica Tsui, Nayvin W. Chew, Peter Yan, Gabriella C. Reeder, Divyashree Kushnoor, Alan Shen, Brittany Davidson, Andrea J. Barczak, Michael Adkisson, Austin Edwards, Mohammad Naser, Kevin C. Barry, Tristan Courau, Taymour Hammoudi, Rafael Arguello, Arjun Arkal Rao, Adam B. Olshen, The Immunoprofiler Consortium, Cathy Cai, Jenny Zhan, Katelyn C. Davis, Robin K. Kelley, Jocelyn S. Chapman, Chloe E. Attreya, Amar Patel, Adlil Daud, Patrick Ha, Aaron A. Diaz, Johannes R. Kratz, Eric A. Collisson, Gabriela K. Fragiadakis, David J. Erle, Alexandre Boissonnas, Saurabh Asthana, Vincent Chan, and Matthew F. Krummel

Published
2021

10. Spatiotemporal Co-Dependency between Macrophages and Exhausted CD8 + T Cells in Cancer

Author

Kelly Kersten, Kenneth H. Hu, Alexis J. Combes, Bushra Samad, Tory Harwin, Arja Ray, Arjun Arkal Rao, En Cai, Kyle Marchuk, Jordan Artichoker, Tristan Courau, Quanming Shi, Julia Belk, Ansuman T. Satpathy, and Matthew F. Krummel

Subjects
History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published
2021

11. Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01.

Author

Weiner, January, Weiner, January, Suwalski, Phillip, Holtgrewe, Manuel, Rakitko, Alexander, Thibeault, Charlotte, Müller, Melina, Patriki, Dimitri, Quedenau, Claudia, Krüger, Ulrike, Ilinsky, Valery, Popov, Iaroslav, Balnis, Joseph, Jaitovich, Ariel, Helbig, Elisa T, Lippert, Lena J, Stubbemann, Paula, Real, Luis M, Macías, Juan, Pineda, Juan A, Fernandez-Fuertes, Marta, Wang, Xiaomin, Karadeniz, Zehra, Saccomanno, Jacopo, Doehn, Jan-Moritz, Hübner, Ralf-Harto, Hinzmann, Bernd, Salvo, Mauricio, Blueher, Anja, Siemann, Sandra, Jurisic, Stjepan, Beer, Juerg H, Rutishauser, Jonas, Wiggli, Benedikt, Schmid, Hansruedi, Danninger, Kathrin, Binder, Ronald, Corman, Victor M, Mühlemann, Barbara, Arjun Arkal, Rao, Fragiadakis, Gabriela K, Mick, Eran, Comet, Consortium, Calfee, Carolyn S, Erle, David J, Hendrickson, Carolyn M, Kangelaris, Kirsten N, Krummel, Matthew F, Woodruff, Prescott G, Langelier, Charles R, Venkataramani, Urmila, García, Federico, Zyla, Joanna, Drosten, Christian, Alice, Braun, Jones, Terry C, Suttorp, Norbert, Witzenrath, Martin, Hippenstiel, Stefan, Zemojtel, Tomasz, Skurk, Carsten, Poller, Wolfgang, Borodina, Tatiana, Pa-Covid, Study Group, Ripke, Stephan, Sander, Leif E, Beule, Dieter, Landmesser, Ulf, Guettouche, Toumy, Kurth, Florian, Heidecker, Bettina, Weiner, January, Weiner, January, Suwalski, Phillip, Holtgrewe, Manuel, Rakitko, Alexander, Thibeault, Charlotte, Müller, Melina, Patriki, Dimitri, Quedenau, Claudia, Krüger, Ulrike, Ilinsky, Valery, Popov, Iaroslav, Balnis, Joseph, Jaitovich, Ariel, Helbig, Elisa T, Lippert, Lena J, Stubbemann, Paula, Real, Luis M, Macías, Juan, Pineda, Juan A, Fernandez-Fuertes, Marta, Wang, Xiaomin, Karadeniz, Zehra, Saccomanno, Jacopo, Doehn, Jan-Moritz, Hübner, Ralf-Harto, Hinzmann, Bernd, Salvo, Mauricio, Blueher, Anja, Siemann, Sandra, Jurisic, Stjepan, Beer, Juerg H, Rutishauser, Jonas, Wiggli, Benedikt, Schmid, Hansruedi, Danninger, Kathrin, Binder, Ronald, Corman, Victor M, Mühlemann, Barbara, Arjun Arkal, Rao, Fragiadakis, Gabriela K, Mick, Eran, Comet, Consortium, Calfee, Carolyn S, Erle, David J, Hendrickson, Carolyn M, Kangelaris, Kirsten N, Krummel, Matthew F, Woodruff, Prescott G, Langelier, Charles R, Venkataramani, Urmila, García, Federico, Zyla, Joanna, Drosten, Christian, Alice, Braun, Jones, Terry C, Suttorp, Norbert, Witzenrath, Martin, Hippenstiel, Stefan, Zemojtel, Tomasz, Skurk, Carsten, Poller, Wolfgang, Borodina, Tatiana, Pa-Covid, Study Group, Ripke, Stephan, Sander, Leif E, Beule, Dieter, Landmesser, Ulf, Guettouche, Toumy, Kurth, Florian, and Heidecker, Bettina

Abstract

BackgroundSince the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing.MethodsWe analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS).FindingsWe describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles.InterpretationHLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2.FundingFunded by Roche Sequencing Solutions, Inc.

Published
2021

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