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

doi:10.1126/science.aba9301

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

Population Health and Occupational Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Merck & Co., Inc., Kenilworth, NJ, USA.
Genetics & Pharmacogenomics, Department of Translational Medicine, Merck & Co., Inc., Boston, MA, USA.
Department of Infectious Disease Epidemiology, Imperial College London School of Public Health, London, UK; Biomedical Research and Training Institute, Harare, Zimbabwe.

Research output: Contribution to journal › Article › peer-review

138 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 language	English
Article number	eaba9301
Pages (from-to)	eaba9301
Journal	Science
Volume	370
Issue number	6513
DOIs	https://doi.org/10.1126/science.aba9301
Publication status	Published - 9 Oct 2020

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Habibi, M. S., Thwaites, R. S., Chang, M., Jozwik, A., Paras, A., Kirsebom, F., Varese, A., Owen, A., Cuthbertson, L., James, P., Tunstall, T., Nickle, D., Hansel, T. T., Moffatt, M. F., Johansson, C., Chiu, C., & Openshaw, P. J. M. (2020). Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection. Science, 370(6513), eaba9301. Article eaba9301. https://doi.org/10.1126/science.aba9301

@article{f9604c74a0e340f595882f7b9a539fb6,

title = "Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection",

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. ",

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

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doi = "10.1126/science.aba9301",

language = "English",

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Habibi, MS, Thwaites, RS, Chang, M, Jozwik, A, Paras, A, Kirsebom, F, Varese, A, Owen, A, Cuthbertson, L, James, P, Tunstall, T, Nickle, D, Hansel, TT, Moffatt, MF, Johansson, C, Chiu, C & Openshaw, PJM 2020, 'Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection', Science, vol. 370, no. 6513, eaba9301, pp. eaba9301. https://doi.org/10.1126/science.aba9301

TY - JOUR

T1 - Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection

AU - Habibi, Maximillian S.

AU - Thwaites, Ryan S.

AU - Chang, Meiping

AU - Jozwik, Agnieszka

AU - Paras, Allan

AU - Kirsebom, Freja

AU - Varese, Augusto

AU - Owen, Amber

AU - Cuthbertson, Leah

AU - James, Phillip

AU - Tunstall, Tanushree

AU - Nickle, David

AU - Hansel, Trevor T.

AU - Moffatt, Miriam F.

AU - Johansson, Cecilia

AU - Chiu, Christopher

AU - Openshaw, Peter J. M.

PY - 2020/10/9

Y1 - 2020/10/9

N2 - 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.

AB - 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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DO - 10.1126/science.aba9301

M3 - Article

SN - 0036-8075

VL - 370

SP - eaba9301

JO - Science

JF - Science

IS - 6513

M1 - eaba9301

ER -

Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection

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