Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection

Maximillian S. Habibi, Ryan S. Thwaites, Meiping Chang, Agnieszka Jozwik, Allan Paras, Freja Kirsebom, Augusto Varese, Amber Owen, Leah Cuthbertson, Phillip James, Tanushree Tunstall, David Nickle, Trevor T. Hansel, Miriam F. Moffatt, Cecilia Johansson*, Christopher Chiu, Peter J.M. Openshaw

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbereaba9301
JournalScience
Volume370
Issue number6513
DOIs
Publication statusPublished - 9 Oct 2020
Externally publishedYes

Bibliographical note

Funding 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).

Publisher Copyright:
© 2020 American Association for the Advancement of Science. All rights reserved.

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