Genomic Circuitry Underlying Immunological Response to Pediatric Acute Respiratory Infection
Sarah E. Henrickson,
Sasikanth Manne,
Douglas V. Dolfi,
Kathleen D. Mansfield,
Kaela Parkhouse,
Rakesh D. Mistry,
Elizabeth R. Alpern,
Scott E. Hensley,
Kathleen E. Sullivan,
Susan E. Coffin,
E. John Wherry
Affiliations
Sarah E. Henrickson
Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Sasikanth Manne
Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
Douglas V. Dolfi
Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
Kathleen D. Mansfield
Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
Kaela Parkhouse
Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
Rakesh D. Mistry
Division of Emergency Medicine, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Elizabeth R. Alpern
Division of Emergency Medicine, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Scott E. Hensley
Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
Kathleen E. Sullivan
Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Susan E. Coffin
Division of Infectious Diseases, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
E. John Wherry
Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
Summary: Acute respiratory tract viral infections (ARTIs) cause significant morbidity and mortality. CD8 T cells are fundamental to host responses, but transcriptional alterations underlying anti-viral mechanisms and links to clinical characteristics remain unclear. CD8 T cell transcriptional circuitry in acutely ill pediatric patients with influenza-like illness was distinct for different viral pathogens. Although changes included expected upregulation of interferon-stimulated genes (ISGs), transcriptional downregulation was prominent upon exposure to innate immune signals in early IFV infection. Network analysis linked changes to severity of infection, asthma, sex, and age. An influenza pediatric signature (IPS) distinguished acute influenza from other ARTIs and outperformed other influenza prediction gene lists. The IPS allowed a deeper investigation of the connection between transcriptional alterations and clinical characteristics of acute illness, including age-based differences in circuits connecting the STAT1/2 pathway to ISGs. A CD8 T cell-focused systems immunology approach in pediatrics identified age-based alterations in ARTI host response pathways. : Henrickson et al. measure transcriptional alterations in blood CD8 T cells from pediatric patients with acute respiratory tract infections and correlate gene modules with clinical characteristics. This approach defines an influenza prediction signature that is effective across ages, revealing age-based alterations in genetic circuitry underlying host responses to influenza. Keywords: influenza, gene expression, rhinovirus, human immunology, CD8 T cell
