Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology
Authors: Hoang Van Phan, Alexandra Tsitsiklis, Cole P. Maguire, Elias K. Haddad, Patrice M. Becker, Seunghee Kim-Schulze, Brian 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 Eckalbar, Leying Guan, Naresh Doni Jayavelu, Steven H. Kleinstein, Florian Krammer, Holden T. Maecker, Al Ozonoff, Bjoern Peters, Nadine Rouphael, Ruth R. Montgomery, Elaine Reed, Joanna Schaenman, Hanno Steen, Ofer Levy, Joann Diray-Arce, Charles R. Langelier, David J. Erle, Carolyn M. Hendrickson, Kirsten N. Kangelaris, Viet Nguyen, Deanna Lee, Suzanna Chak, Rajani Ghale, Ana Gonzalez, Alejandra Jauregui, Carolyn Leroux, Luz Torres Altamirano, Ahmad Sadeed Rashid, Andrew Willmore, Prescott G. Woodruff, Matthew F. Krummel, Sidney Carrillo, Alyssa Ward, Ravi Patel, Michael Wilson, Ravi Dandekar, Bonny Alvarenga, Jayant Rajan, Andrew W. 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 C. Hurley, Janelle N. Geltman, Nadia Siles, Jacob E. Rogers, Michele A. Kutzler, Mariana Bernui, Gina Cusimano, Jennifer Connors, Kyra Woloszczuk, David Joyner, Carolyn Edwards, Edward Lin, Nataliya Melnyk, Debra L. Powell, James N. Kim, I. Michael Goonewardene, Brent Simmons, Cecilia M. Smith, Mark Martens, Brett Croen, Nicholas C. Semenza, Mathew 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 Fernandez-Sesma, Viviana Simon, Harm Van Bakel, Ana Silvia Gonzalez-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, Maria Carolina Bermúdez González, Lubbertus C. F. Mulder, Katherine Beach, Benoit Fatou, Kinga Smolen, Arthur Viode, Simon van Haren, Meenakshi Jha, Alvin Kho, Carly E. Milliren, Ana C. Chang, Kerry McEnaney, Brenda Barton, Claudia Lentucci, Maimouna Murphy, Mehmet Saluvan, Tanzia Shaheen, Shanshan Liu, Caitlin Syphurs, Marisa Albert, Arash Nemati Hayati, Robert 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 Brito, Jessica Rothman, Nathan Grubaugh, Albert I. Ko, David A. Hafler, Albert C. Shaw, Jeremy Gygi, Shrikant Pawar, Anna Konstorum, Ernie Chen, Chris Cotsapas, Xiaomei Wang, Leqi Xu, Charles Dela Cruz, Akiko Iwasaki, Subhasis Mohanty, Allison Nelson, Yujiao Zhao, Shelli Farhadian, Hiromitsu Asashima, Bali Pulendran, R. Kari C. Nadeau, Yael Rosenberg-Hasson, Michael Leipold, Natalia Sigal, Angela 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 Sekaly, Slim Fourati, Grace A. McComsey, Paul Harris, Scott Sieg, Susan Pereira Ribeiro, James A. Overton, Adeeb Rahman, Scott R. Hutton, Greg Michelotti, Kari Wong, Vicki Seyfert-Margolis, Jordan P. Metcalf, Nelson I. Agudelo Higuita, Lauren Sinko, J. Leland Booth, William B. Messer, Catherine L. Hough, Sarah Siegel, Peter Sullivan, Zhengchun Lu, Monica Kraft, Chris Bime, Jarrod Mosier, Heidi Erickson, Ron Schunk, Hiroki Kimura, Michelle Conway, Mark A. Atkinson, Scott C. Brakenridge, Ricardo F. Ungaro, Brittany Roth Manning, Jordan Oberhaus, Faheem W. Guirgis, Brittany Borresen, Matthew L. Anderson
Journal: Science Translational Medicine (2024)

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.