Journal
SCIENCE
Volume 370, Issue 6513, Pages 188-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aba9301
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Funding
- Wellcome Trust [087805/Z/08/Z, 102126/B/13/Z, 109058/Z/15/Z]
- Medical Research Council HIC-Vac network [MR/R005982/1]
- RSV Consortium in Europe (RESCEU) Horizon 2020 Framework Grant [116019]
- UK National Institute for Health Research (NIHR) Comprehensive Local Research Networks (CLRNs)
- European Respiratory Society
- Asociacion Latinoamericana de Torax joint long-term Research Fellowship 2019 (LTRF) [20190100546]
- NIHR Senior Investigator award
- Biomedical Research Centre (NIHR Imperial BRC)
- Health Protection Research Unit in Respiratory Infections at Imperial College London (NIHR HPRU RI)
- Wellcome Trust [109058/Z/15/Z, 087805/Z/08/Z, 102126/B/13/Z] Funding Source: Wellcome Trust
- MRC [G0902266, MR/T50256X/1, MR/R502121/1, MR/R005982/1] Funding Source: UKRI
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The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17- and tumor necrosis factor-related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8(+) T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure.
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