Host Respiratory Transcriptome Signature Associated with Poor Outcome in Children with Influenza–Staphylococcus aureus Pneumonia

Author:

Britto Carl123,Mohorianu Irina24ORCID,Yeung Tracy5,Cheung Elaine5,Novak Tanya67,Hall Mark W8,Mourani Peter M9,Weiss Scott L10,Thomas Neal J11,Markovitz Barry12,Randolph Adrienne G6713ORCID,Moffitt Kristin L513ORCID

Affiliation:

1. Department of Pediatrics, Boston Children’s Hospital , Boston, Massachusetts , USA

2. Oxford Vaccine Group, Department of Paediatrics, University of Oxford , United Kingdom

3. Division of Infectious Disease, St John’s Research Institute , Bengaluru , India

4. Wellcome-MRC Cambridge, Stem Cell Institute, University of Cambridge , United Kingdom

5. Division of Infectious Diseases, Boston Children’s Hospital , Boston, Massachusetts , USA

6. Department of Anesthesia, Critical Care and Pain Medicine, Boston Children’s Hospital , Boston, Massachusetts , USA

7. Department of Anesthesia, Harvard Medical School , Boston, Massachusetts , USA

8. Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital , Columbus, Ohio , USA

9. Department of Pediatrics, Section of Critical Care Medicine, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute , Little Rock, Arkansas , USA

10. Division of Critical Care, Department of Anesthesiology and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine , Philadelphia, Pennsylvania , USA

11. Department of Pediatrics, Penn State Hershey Children’s Hospital, Penn State University College of Medicine , Hershey, Pennsylvania , USA

12. Department of Anesthesiology Critical Care Medicine, Children’s Hospital Los Angeles , Los Angeles, California , USA

13. Department of Pediatrics, Harvard Medical School , Boston, Massachusetts , USA

Abstract

Abstract Respiratory coinfection of influenza with Staphylococcus aureus often causes severe disease; methicillin-resistant S. aureus (MRSA) coinfection is frequently fatal. Understanding disease pathogenesis may inform therapies. We aimed to identify host and pathogen transcriptomic (messenger RNA) signatures from the respiratory compartment of pediatric patients critically ill with influenza–S. aureus coinfection (ISAC), signatures that predict worse outcomes. Messenger RNA extracted from endotracheal aspirate samples was evaluated for S. aureus and host transcriptomic biosignatures. Influenza-MRSA outcomes were worse, but of 190 S. aureus virulence-associated genes, 6 were differentially expressed between MRSA-coinfected versus methicillin-susceptible S. aureus–coinfected patients, and none discriminated outcome. Host gene expression in patients with ISAC was compared with that in patients with influenza infection alone. Patients with poor clinical outcomes (death or prolonged multiorgan dysfunction) had relatively reduced expression of interferons and down-regulation of interferon γ–induced immune cell chemoattractants CXCL10 and CXCL11. In ISAC, airway host but not pathogen gene expression profiles predicted worse clinical outcomes.

Funder

BCH Translational Research Program

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Immunology and Allergy

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