Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection

Abstract

Despite the prevalence and clinical importance of influenza, its long-term effect on lung immunity is unclear. Here we describe that following viral clearance and clinical recovery, at 1 month after infection with influenza, mice are better protected from Streptococcus pneumoniae infection due to a population of monocyte-derived alveolar macrophages (AMs) that produce increased interleukin-6. Influenza-induced monocyte-derived AMs have a surface phenotype similar to resident AMs but display a unique functional, transcriptional and epigenetic profile that is distinct from resident AMs. In contrast, influenza-experienced resident AMs remain largely similar to naive AMs. Thus, influenza changes the composition of the AM population to provide prolonged antibacterial protection. Monocyte-derived AMs persist over time but lose their protective profile. Our results help to understand how transient respiratory infections, a common occurrence in human life, can constantly alter lung immunity by contributing monocyte-derived, recruited cells to the AM population.

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Fig. 1: At 1 month post-influenza, mice are more protected against S. pneumoniae infection and have an increased population of AMs that confer resistance.
Fig. 2: AMs from post-influenza mice produce increased IL-6 that confers protection from S. pneumoniae infection.
Fig. 3: CCR2-dependent monocyte recruitment contributes to the population of AMs and their altered functional profile 1 month after infection with influenza.
Fig. 4: Quantifying the contribution of CCR2-dependent monocytes to AMs and their cytokine production 1 month after infection with influenza.
Fig. 5: Recruited macrophages are distinct in their expression and chromatin profile, relative to resident macrophages, 1 month after infection with influenza.
Fig. 6: Following TLR stimulation, origin determines gene expression, chromatin profile and Il6 gene accessibility.
Fig. 7: Monocyte-derived AMs persist for 2 months after infection with influenza, but do not produce increased IL-6 and afford bacterial protection.

Data availability

Sequencing data are available in GEO under accession code GSE120543.

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Acknowledgements

We are grateful to S. Rose-John (Kiel University) for the kind gift of anti-IL-6, to C. Reis e Sousa and G. Stockinger for reading the manuscript and A. Warnatsch for initial help with reactive oxygen species measurements. This work benefited from data assembled by the ImmGen consortium. We thank the Advanced Sequencing, Flow Cytometry, Biological Research and Histopathology facilities of the Francis Crick Institute for excellent support. This study was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001206), the UK Medical Research Council (FC001206) and the Wellcome Trust (FC001206). Support by MRC grant U117597139 (S.C. and A.W.) and a BBSRC-GSK-funded case studentship BB/L502315/1 (H.A.) is gratefully acknowledged.

Author information

H.A, S.C., J.K. and A.W. designed the experiments; H.A., J.K. and S.C. performed the experiments; H.A., J.K., S.C., H.P. and G.K. analyzed data; H.A., S.C., H.P., E.M.H., S.B. and A.W. interpreted data; M.M. provided vital reagents; S.C., H.P., E.M.H. and S.B. contributed to manuscript writing; H.A. and A.W. wrote the manuscript.

Correspondence to Andreas Wack.

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Competing interests

E.M.H. and S.B. were employees of GSK at the time of this study. The other authors declare that they have no conflict of interest.

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Peer review information Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Aegerter, H., Kulikauskaite, J., Crotta, S. et al. Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection. Nat Immunol 21, 145–157 (2020). https://doi.org/10.1038/s41590-019-0568-x

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