Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology
Authors: Phan Hoang Van , Tsitsiklis Alexandra , Maguire Cole P. , Haddad Elias K. , Becker Patrice M. , Kim-Schulze Seunghee , Lee Brian , Chen Jing , Hoch Annmarie , Pickering Harry , van Zalm Patrick , Altman Matthew C. , Augustine Alison D. , Calfee Carolyn S. , Bosinger Steve , Cairns Charles B. , Eckalbar Walter , Guan Leying , Jayavelu Naresh Doni , Kleinstein Steven H. , Krammer Florian , Maecker Holden T. , Ozonoff Al , Peters Bjoern , Rouphael Nadine ,   IMPACC Network, Montgomery Ruth R. , Reed Elaine , Schaenman Joanna , Steen Hanno , Levy Ofer , Diray-Arce Joann , Langelier Charles R. , Erle David J. , Hendrickson Carolyn M. , Kangelaris Kirsten N. , Nguyen Viet , Lee Deanna , Chak Suzanna , Ghale Rajani , Gonzalez Ana , Jauregui Alejandra , Leroux Carolyn , Altamirano Luz Torres , Rashid Ahmad Sadeed , Willmore Andrew , Woodruff Prescott G. , Krummel Matthew F. , Carrillo Sidney , Ward Alyssa , Patel Ravi , Wilson Michael , Dandekar Ravi , Alvarenga Bonny , Rajan Jayant , Schroeder Andrew W. , Fragiadakis Gabriela K. , Mick Eran , Guerrero Yanedth Sanchez , Love Christina , Maliskova Lenka , Adkisson Michael , Ehrlich Lauren I. R. , Melamed Esther , Rousseau Justin F. , Hurley Kerin C. , Geltman Janelle N. , Siles Nadia , Rogers Jacob E. , Kutzler Michele A. , Bernui Mariana , Cusimano Gina , Connors Jennifer , Woloszczuk Kyra , Joyner David , Edwards Carolyn , Lin Edward , Melnyk Nataliya , Powell Debra L. , Kim James N. , Goonewardene I. Michael , Simmons Brent , Smith Cecilia M. , Martens Mark , Croen Brett , Semenza Nicholas C. , Bell Mathew R. , Furukawa Sara , McLin Renee , Tegos George P. , Rogowski Brandon , Mege Nathan , Ulring Kristen , Holland Steven M. , Rosen Lindsey B. , Lee Serena , Vaysman Tatyana , Fernandez-Sesma Ana , Simon Viviana , Van Bakel Harm , Gonzalez-Reiche Ana Silvia , Qi Jingjing , Carreño Juan Manuel , Singh Gagandeep , Raskin Ariel , Tcheou Johnstone , Khalil Zain , van de Guchte Adriana , Farrugia Keith , Khan Zenab , Kelly Geoffrey , Srivastava Komal , Eaker Lily , Bermúdez González Maria Carolina , Mulder Lubbertus C. F. , Beach Katherine , Fatou Benoit , Smolen Kinga , Viode Arthur , van Haren Simon , Jha Meenakshi , Kho Alvin , Milliren Carly E. , Chang Ana C. , McEnaney Kerry , Barton Brenda , Lentucci Claudia , Murphy Maimouna , Saluvan Mehmet , Shaheen Tanzia , Liu Shanshan , Syphurs Caitlin , Albert Marisa , Hayati Arash Nemati , Bryant Robert , Abraham James , Salehi-Rad Ramin , Rivera Adreanne M. , Sen Subha , Elashoff David , Ward Dawn C. , Presnell Scott , Kohr Bernard , Arnett Azlann , Boddapati Arun K. , Tharp Greg K. , Pellegrini Kathryn L. , Johnson Brandi , Panganiban Bernadine , Huerta Christopher , Anderson Evan J. , Samaha Hady , Sevransky Jonathan , Bristow Laurel , Beagle Elizabeth , Cowan David , Hamilton Sydney , Hodder Thomas , Esserman Denise , Brito Anderson , Rothman Jessica , Grubaugh Nathan , Ko Albert I. , Hafler David A. , Shaw Albert C. , Gygi Jeremy , Pawar Shrikant , Konstorum Anna , Chen Ernie , Cotsapas Chris , Wang Xiaomei , Xu Leqi , Dela Cruz Charles , Iwasaki Akiko , Mohanty Subhasis , Nelson Allison , Zhao Yujiao , Farhadian Shelli , Asashima Hiromitsu , Pulendran Bali , Nadeau R. Kari C. , Rosenberg-Hasson Yael , Leipold Michael , Sigal Natalia , Rogers Angela , Fernandez Andrea , Manohar Monali , Do Evan , Chang Iris , Vita Randi , Westendorf Kerstin , Corry David B. , Kheradmand Farrah , Song Li-Zhen , Nelson Ebony , Baden Lindsey R. , Mendez Kevin , Lasky-Su Jessica , Tong Alexandra , Rooks Rebecca , Sekaly Rafick-Pierre , Fourati Slim , McComsey Grace A. , Harris Paul , Sieg Scott , Ribeiro Susan Pereira , Overton James A. , Rahman Adeeb , Hutton Scott R. , Michelotti Greg , Wong Kari , Seyfert-Margolis Vicki , Metcalf Jordan P. , Agudelo Higuita Nelson I. , Sinko Lauren , Booth J. Leland , Messer William B. , Hough Catherine L. , Siegel Sarah , Sullivan Peter , Lu Zhengchun , Kraft Monica , Bime Chris , Mosier Jarrod , Erickson Heidi , Schunk Ron , Kimura Hiroki , Conway Michelle , Atkinson Mark A. , Brakenridge Scott C. , Ungaro Ricardo F. , Manning Brittany Roth , Oberhaus Jordan , Guirgis Faheem W. , Borresen Brittany , Anderson Matthew L. 
Published: April 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.