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

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.