Abstract
Background Cigarette smokers are at increased risk of acquiring influenza, developing severe disease, and requiring hospitalization/ICU admission following infection. However, immune mechanisms underlying this predisposition are incompletely understood, and therapeutic strategies for influenza are limited.
Methods We used a mouse model of concurrent cigarette smoke exposure and H1N1 influenza infection, colony-stimulating factor (CSF)3 supplementation/receptor (CSF3R) blockade, and single-cell RNA sequencing (scRNAseq) to investigate this relationship.
Results Cigarette smoke exposure exacerbated features of viral pneumonia such as edema, hypoxemia, and pulmonary neutrophilia. Smoke-exposed, infected mice demonstrated an increase in viral (v)RNA, but not replication-competent viral particles, relative to infection-only controls. Interstitial rather than airspace neutrophilia positively predicted morbidity in smoke-exposed, infected mice. Screening of pulmonary cytokines using a novel dysregulation score identified an exacerbated expression of CSF3 and interleukin (IL)-6 in the context of smoke exposure and influenza. Recombinant (r)CSF3 supplementation during influenza aggravated morbidity, hypothermia, and edema, while anti-CSF3R treatment of smoke-exposed infected mice improved alveolar-capillary barrier function. scRNAseq delineated a shift in the distribution of Csf3+ cells towards neutrophils in the context of cigarette smoke and influenza. However, although smoke-exposed lungs were enriched for infected, highly-activated neutrophils, gene signatures of these cells largely reflected an exacerbated form of typical influenza with select unique regulatory features.
Conclusion This work provides novel insight into the mechanisms by which cigarette smoke exacerbates influenza infection, unveiling potential therapeutic targets (e.g. excess vRNA accumulation, edematous CSF3R signaling) for use in this context, and potential limitations for clinical rCSF3 therapy during viral infectious disease.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Miller reports consulting fees for scientific advisory board participation from Seqirus and Medicago (influenza vaccines); lecture honoraria for lunch-and-learn on COVID-19 vaccines from Boehringer-Ingelheim; outside the submitted work.
Conflict of interest: Ask reports grants from Alkermes, Prometic, GSK, Canadian Institute for Health Research, Pharmaxis, Indalo, Unity Biotechnology, Canadian Pulmonary Fibrosis Association, Collaborative Health Research Projects, Pieris Pharmaceuticals, Bold Therapeutics, Pliant, CSL Behring, Boehringer Ingelheim; lecture honoraria from Boehringer Ingelheim; travel support from Boehringer Ingelheim; outside the submitted work.
Conflict of interest: Kuebler reports grant-in-aid from Canadian Institutes of Health Research (CIHR), during the course of the present study; grants-in-aid from German Research Foundation (DFG), German Ministry for Research and Education (BMBF), Berlin Institute of Health (BIH), German Centre for Cardiovascular Research (DZHK); outside the submitted work.
Conflict of interest: Stampfli reports support for the present manuscript from Canadian Institutes of Health Research; grants from RespiVert Pharmaceuticals, Canadian Heart and Stroke Foundation, Ontario Thoracic Society; consulting fees from Boehringer Ingelheim; lecture honoraria from AstraZeneca; MTA for monoclonal antibody to block G-CSF from CSL Behring and is employed with CSL Behring since January 2020; outside the submitted work.
Conflict of interest: Dr. McGrath has nothing to disclose.
Conflict of interest: Dr. Vanderstocken has nothing to disclose.
Conflict of interest: Dr. Dvorkin-Gheva has nothing to disclose.
Conflict of interest: Dr. Cass has nothing to disclose.
Conflict of interest: Dr. Afkhami has nothing to disclose.
Conflict of interest: Dr. Fantauzzi has nothing to disclose.
Conflict of interest: Dr. Thayaparan has nothing to disclose.
Conflict of interest: Dr. Reihani has nothing to disclose.
Conflict of interest: Dr. Wang has nothing to disclose.
Conflict of interest: Dr. Beaulieu has nothing to disclose.
Conflict of interest: Dr. Shen has nothing to disclose.
Conflict of interest: Dr. Morissette has nothing to disclose.
Conflict of interest: Dr. Jiménez-Saiz has nothing to disclose.
Conflict of interest: Dr. Revill has nothing to disclose.
Conflict of interest: Dr. Tabuchi has nothing to disclose.
Conflict of interest: Dr. Zabini has nothing to disclose.
Conflict of interest: Dr. Lee has nothing to disclose.
Conflict of interest: Dr. Richards has nothing to disclose.
Conflict of interest: Dr. Simpson has nothing to disclose.
- Received July 22, 2021.
- Accepted December 29, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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