Detection of respiratory syncytial virus defective genomes in nasal secretions is associated with distinct clinical outcomes

• Type of Material: Article
• Authors: Sébastien A Felt, University of Pennsylvania; Yan Sun, University of Pennsylvania; Agnieszka Jozwik, Imperial College London; Aallan Paras, Imperial College London; Maximilllian S Habibi, Imperial College London; David Nickle, Merck & Co., Inc.; Larry Anderson, Emory University; Emma Achouri, Washington University; Kristen A Feemster, Childrens Hospital of Philadelphia; Ana María Cárdenas, Childrens Hospital of Philadelphia; Kedir N Turi, Vanderbilt University; Meiping Chang, Merck & Co., Inc.; Tina V Hartert, Vanderbilt University; Shaon Sengupta, University of Pennsylvania; Christopher Chiu, Imperial College London; Carolina B Lopez, University of Pennsylvania
• Language: English
• Date: 2021-04-01
• Publisher: NATURE RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41564-021-00882-3
• Title of Journal or Parent Work: NATURE MICROBIOLOGY
• Volume: 6
• Issue: 5
• Start Page: 672
• End Page: +
• Grant/Funding Information: Funding was received from NIH R01 AI137092 and R01 AI137062 for C.B.L., NIH U19 AI095227, UL1 RR024975 and K24 AI077930 for T.H., and the Medical Research Council (G0902266) and Wellcome Trust (087805/Z/08/Z) for C.C. C.C. is supported by the Biomedical Research Centre award to Imperial College Healthcare NHS Trust. Infrastructure support for C.C. was provided by the NIHR Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
• Keywords: Microbiology; Science & Technology; Life Sciences & Biomedicine

Abstract

Respiratory syncytial virus (RSV) causes respiratory illness in children, immunosuppressed individuals and the elderly. However, the viral factors influencing the clinical outcome of RSV infections remain poorly defined. Defective viral genomes (DVGs) can suppress virus replication by competing for viral proteins and by stimulating antiviral immunity. We studied the association between detection of DVGs of the copy-back type and disease severity in three RSV A-confirmed cohorts. In hospitalized children, detection of DVGs in respiratory samples at or around the time of admission associated strongly with more severe disease, higher viral load and a stronger pro-inflammatory response. Interestingly, in experimentally infected adults, the presence of DVGs in respiratory secretions differentially associated with RSV disease severity depending on when DVGs were detected. Detection of DVGs early after infection associated with low viral loads and mild disease, whereas detection of DVGs late after infection, especially if DVGs were present for prolonged periods, associated with high viral loads and severe disease. Taken together, we demonstrate that the kinetics of DVG accumulation and duration could predict clinical outcome of RSV A infection in humans, and thus could be used as a prognostic tool to identify patients at risk of worse clinical disease.