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.
Bibliographical noteFunding Information:
The authors gratefully acknowledge support from the Wellcome Trust (087805/Z/08/Z, 102126/B/13/Z, and 109058/ Z/15/Z); The Medical Research Council HIC-Vac network (MR/ R005982/1); RSV Consortium in Europe (RESCEU) Horizon 2020 Framework Grant 116019; the UK National Institute for Health Research (NIHR) Comprehensive Local Research Networks (CLRNs); European Respiratory Society and the Asociaci?n Latinoamericana de T?rax joint long-term Research Fellowship 2019 (LTRF 201901-00546); an NIHR Senior Investigator award; the Biomedical Research Centre (NIHR Imperial BRC); and the Health Protection Research Unit in Respiratory Infections at Imperial College London (NIHR HPRU RI).
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