Age-associated differences in mucosal and systemic host responses to SARS-CoV-2 infection

Jillian H. Hurst, Aditya A. Mohan, Trisha Dalapati, Ian A. George, Jhoanna N. Aquino, Debra J. Lugo, Trevor S. Pfeiffer, Javier Rodriguez, Alexandre T. Rotta, Nicholas A. Turner, Thomas W. Burke, Micah T. McClain, Ricardo Henao, C. Todd DeMarco, Raul Louzao, Thomas N. Denny, Kyle M. Walsh, Zhaohui Xu, Asuncion Mejias, Octavio Ramilo, Christopher W. Woods and Matthew S. Kelly ()
Additional contact information
Jillian H. Hurst: Duke University School of Medicine
Aditya A. Mohan: Duke University School of Medicine
Trisha Dalapati: Duke University School of Medicine
Ian A. George: Duke University School of Medicine
Jhoanna N. Aquino: Duke University School of Medicine
Debra J. Lugo: Duke University School of Medicine
Trevor S. Pfeiffer: Duke University School of Medicine
Javier Rodriguez: Duke University School of Medicine
Alexandre T. Rotta: Duke University School of Medicine
Nicholas A. Turner: Duke University School of Medicine
Thomas W. Burke: Duke University School of Medicine
Micah T. McClain: Duke University School of Medicine
Ricardo Henao: Duke University
C. Todd DeMarco: Duke University School of Medicine
Raul Louzao: Duke University School of Medicine
Thomas N. Denny: Duke University School of Medicine
Kyle M. Walsh: Duke University School of Medicine
Zhaohui Xu: St. Jude Children’s Research Hospital
Asuncion Mejias: St. Jude Children’s Research Hospital
Octavio Ramilo: St. Jude Children’s Research Hospital
Christopher W. Woods: Duke University School of Medicine
Matthew S. Kelly: Duke University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Age is among the strongest risk factors for severe outcomes from SARS-CoV-2 infection. Here we describe upper respiratory tract (URT) and peripheral blood transcriptomes of 202 participants (age range of 1 week to 83 years), including 137 non-hospitalized individuals with mild SARS-CoV-2 infection and 65 healthy individuals. Among healthy children and adolescents, younger age is associated with higher URT expression of innate and adaptive immune pathways. SARS-CoV-2 infection induces broad upregulation of URT innate and adaptive immune responses among children and adolescents. Peripheral blood responses among SARS-CoV-2-infected children and adolescents are dominated by interferon pathways, while upregulation of myeloid activation, inflammatory, and coagulation pathways is observed only in adults. Among SARS-CoV-2-infected individuals, fever is associated with blunted URT immune responses and more pronounced systemic immune activation. These findings demonstrate that immune responses to SARS-CoV-2 differ across the lifespan, from distinct signatures in childhood and adolescence to age-associated alterations in adults.

Date: 2025
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DOI: 10.1038/s41467-025-57655-3

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