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Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology

2024; American Association for the Advancement of Science; Volume: 16; Issue: 743 Linguagem: Inglês

10.1126/scitranslmed.adj5154

1946-6242

Hoang Van Phan, Alexandra Tsitsiklis, Cole Maguire, Elias K. Haddad, Patrice M. Becker, Seunghee Kim‐Schulze, Brian Hyohyoung Lee, Jing Chen, Annmarie Hoch, Harry Pickering, Patrick van Zalm, Matthew C. Altman, Alison D. Augustine, Carolyn S. Calfee, Steve Bosinger, Charles B. Cairns, Walter L. Eckalbar, Leying Guan, Naresh Doni Jayavelu, Steven H. Kleinstein, Florian Krammer, Holden T. Maecker, Al Ozonoff, Bjoern Peters, Nadine Rouphael, Ruth R. Montgomery, Elaine F. Reed, Joanna Schaenman, Hanno Steen, Ofer Levy, Joann Diray‐Arce, Charles Langelier, David J. Erle, Carolyn M. Hendrickson, Kirsten N. Kangelaris, Nguyễn Hoàng Việt, Deanna Lee, Suzanna Chak, Rajani Ghale, Ana Gonzalez, Alejandra Jáuregui, Carolyn Leroux, Luz Torres Altamirano, Ahmad Sadeed Rashid, Andrew Willmore, Prescott G. Woodruff, Matthew F. Krummel, Sidney Carrillo, Alyssa Ward, Ravi K. Patel, Michael R. Wilson, Ravi Dandekar, Bonny D. Alvarenga, Jayant V. Rajan, Andrew Schroeder, Gabriela K. Fragiadakis, Eran Mick, Yanedth Sanchez Guerrero, Christina Love, Lenka Maliskova, Michael Adkisson, Lauren I. R. Ehrlich, Esther Melamed, Justin F. Rousseau, Kerin Hurley, Janelle Geltman, Nadia Siles, Jacob E. Rogers, Michele A. Kutzler, Mariana Bernui, Gina Cusimano, Jennifer Connors, Kyra Woloszczuk, David Joyner, Carolyn Pope Edwards, Edward Lin, Nataliya Melnyk, Debra Powell, James N. Kim, I. Michael Goonewardene, Brent Simmons, Cecilia M. Smith, Mark G. Martens, Brett Croen, Nicholas C. Semenza, Matthew R. Bell, Sara Furukawa, Renee McLin, George P. Tegos, Brandon Rogowski, Nathan Mege, Kristen Ulring, Steven M. Holland, Lindsey B. Rosen, Serena Lee, Tatyana Vaysman, Ana Fernández-Sesma, Viviana Simon, Harm van Bakel, Ana S. González-Reiche, Jingjing Qi, Juan Manuel Carreño, Gagandeep Singh, Ariel Raskin, Johnstone Tcheou, Zain Khalil, Adriana van de Guchte, Keith Farrugia, Zenab Khan, Geoffrey Kelly, Komal Srivastava, Lily Eaker, María González, Lubbertus C. F. Mulder, Katherine Beach, Benoit Fatou, Kinga K. Smolen, Arthur Viodé, Simon van Haren, Meenakshi Jha, Alvin T. Kho, Carly E. Milliren, Ana C. Chang, Kerry McEnaney, Brenda Barton, Claudia Lentucci, Maimouna D. Murphy, Mehmet Saluvan, Tanzia Shaheen, Shanshan Liu, Caitlin Syphurs, Albert Marisa, Arash Nemati Hayati, Robert W. Bryant, James Abraham, Ramin Salehi‐Rad, Adreanne M. Rivera, Subha Sen, David Elashoff, Dawn C. Ward, Scott Presnell, Bernard Kohr, Azlann Arnett, Arun K. Boddapati, Greg K. Tharp, Kathryn L. Pellegrini, Brandi Johnson, Bernadine Panganiban, Christopher Huerta, Evan J. Anderson, Hady Samaha, Jonathan Sevransky, Laurel Bristow, Elizabeth Beagle, David Cowan, Sydney Hamilton, Thomas Hodder, Denise Esserman, Anderson F. Brito, Jessica E. Rothman, Nathan D. Grubaugh, Albert I. Ko, David A. Hafler, Albert C. Shaw, Jeremy P. Gygi, Shrikant Pawar, Anna Konstorum, Ernie Chen, Chris Cotsapas, Xiaomei Wang, Leqi Xu, Charles S. Dela Cruz, Akiko Iwasaki, Subhasis Mohanty, Allison Nelson, Yujiao Zhao, Shelli Farhadian, Hiromitsu Asashima, Bali Pulendran, R. Kari C. Nadeau, Yael Rosenberg‐Hasson, Michael D. Leipold, Natalia Sigal, Angela J. Rogers, Andrea Fernandez, Monali Manohar, Evan Do, Iris Chang, Randi Vita, Kerstin Westendorf, David B. Corry, Farrah Kheradmand, Li-Zhen Song, Ebony Nelson, Lindsey R. Baden, Kevin Mendez, Jessica Lasky‐Su, Alexandra Tong, Rebecca Rooks, Rafick‐Pierre Sékaly, Slim Fourati, Grace A. McComsey, Paul Harris, Scott F. Sieg, Susan Pereira Ribeiro, James A. Overton, Adeeb Rahman, Scott R. Hutton, Gregory A. Michelotti, Kari E. Wong, Vicki Seyfert‐Margolis, Jordan P. Metcalf, Nelson Iván Agudelo Higuita, Lauren A. Sinko, J. Leland Booth, William B. Messer, Catherine L. Hough, Sarah Siegel, Peter Sullivan, Zhengchun Lu, Monica Kraft, Chris Bime, Jarrod Mosier, Heidi L. Erickson, Ron Schunk, Hiroki Kimura, Michelle Conway, Mark A. Atkinson, Scott C. Brakenridge, Ricardo Ungaro, Brittany Roth Manning, Jordan Oberhaus, Faheem W. Guirgis, Brittany Borresen, Matthew L. Anderson,

Immune responses and vaccinations

Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between 18 and 96 years old. We performed mass cytometry, serum protein profiling, anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays, and blood and nasal transcriptomics. We found that older age correlated with increased SARS-CoV-2 viral abundance upon hospital admission, delayed viral clearance, and increased type I interferon gene expression in both the blood and upper airway. We also observed age-dependent up-regulation of innate immune signaling pathways and down-regulation of adaptive immune signaling pathways. Older adults had lower naïve T and B cell populations and higher monocyte populations. Over time, older adults demonstrated a sustained induction of pro-inflammatory genes and serum chemokines compared with younger individuals, suggesting an age-dependent impairment in inflammation resolution. Transcriptional and protein biomarkers of disease severity differed with age, with the oldest adults exhibiting greater expression of pro-inflammatory genes and proteins in severe disease. Together, our study finds that aging is associated with impaired viral clearance, dysregulated immune signaling, and persistent and potentially pathologic activation of pro-inflammatory genes and proteins.