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.
N1 - Publisher Copyright:
© 2020 American Association for the Advancement of Science. All rights reserved.
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.
UR - http://www.scopus.com/inward/record.url?scp=85092683739&partnerID=8YFLogxK
U2 - 10.1126/science.aba9301
DO - 10.1126/science.aba9301
M3 - Article
C2 - 33033192
AN - SCOPUS:85092683739
SN - 0036-8075
VL - 370
JO - Science
JF - Science
IS - 6513
M1 - eaba9301
ER -