Microbiota-Driven Tonic Interferon Signals in Lung Stromal Cells Protect from Influenza Virus Infection
Open accessAbstract
Type I interferon (IFNα/β) pathways are fine-tuned to elicit antiviral protection while minimizing immunopathology; however, the initiating stimuli, target tissues, and underlying mechanisms are unclear. Using models of physiological and dysregulated IFNα/β receptor (IFNAR1) surface expression, we show here that IFNAR1-dependent signals set the steady-state IFN signature in both hematopoietic and stromal cells. Increased IFNAR1 levels promote a lung environment refractory to early influenza virus replication by elevating the baseline interferon signature. Commensal microbiota drive the IFN signature specifically in lung stroma, as shown by antibiotic treatment and fecal transplantation. Bone marrow chimera experiments identify lung stromal cells as crucially important for early antiviral immunity and stroma-immune cell interaction for late antiviral resistance. We propose that the microbiota-driven interferon signature in lung epithelia impedes early virus replication and that IFNAR1 surface levels fine-tune this signature. Our findings highlight the interplay between bacterial and viral exposure, with important implications for antibiotic use.
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Additional rodent studies have shown that the microbiome plays an important role in mediating IFN signatures in lung tissue by inducing an early refractory environment for influenza virus replication, thus reducing early infection with influenza virus.
“Additional studies in rodents have shown that the microbiome plays an important role in mediating IFN signatures in the lung tissue by inducing an early refractory environment for influenza virus replication, thus reducing early infection with the influenza virus [160].”
From The Potential Impact of Probiotics on Human Health: An Update on Their Health-Promoting Properties (2024) · cites this paper as [160]
The gastrointestinal microbiota signals to lung stromal cells to keep them in an interferon-primed state, protecting them from influenza virus infection through early blunting of the viral life cycle.
“Bradley et al. demonstrated that the GI microbiota signals to lung stromal cells to keep them in an IFN-primed state thus affording them protection from influenza virus infection through early blunting of the viral life cycle (Bradley et al., 2019).”
From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Bradley et al., 2019
Oral antibiotic treatment impairs this antiviral mechanism in rodents and thus increases susceptibility to viral infections, and this impairment is reversed with fecal transplantation from control mice.
“Oral antibiotic treatment in this study was shown to impair this antiviral mechanism in rodents and thus increase susceptibility to viral infections. Intriguingly, this antibiotic induced impairment was shown to be reversed with fecal transplantation from control mice (Bradley et al., 2019).”
From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Bradley et al., 2019
Additional rodent studies have shown a role for the microbiome in mediating IFN signatures in lung tissue, which can induce an environment refractory to early influenza virus replication thus blunting early influenza virus infection.
“Additional rodent studies have shown a role for the microbiome in mediating IFN signatures in lung tissue, which can induce an environment refractory to early influenza virus replication thus blunting early influenza virus infection (Bradley et al., 2019).”
From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Bradley et al., 2019
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References 67 · Cited by 313
- Authors
- Bradley, K. C., Finsterbusch, K., Schnepf, D., Crotta, S., Llorian, M., Davidson, S., Fuchs, S. Y., Staeheli, P., & Wack, A.
- Affiliations
- The Francis Crick Institute (GB)
- University of Freiburg (DE)
- University of Pennsylvania (US)
- Corresponding author
- Wack, Andreas
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 28
- Issue
- 1
- Pages
- 245-256.e4
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2953542823
- Cited by
- 313
- References
- 67
- Citations by year
- 2026: 25 · 2025: 21 · 2024: 41 · 2023: 47 · 2022: 58 · 2021: 65 · 2020: 55 · 2019: 1
- FWCI
- 17.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- The Francis Crick Institute (cc-by)
- Funders
- Francis Crick Institute
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- type I interferon, IFNAR1, lung stromal cells, commensal microbiota, influenza, antiviral immunity, antibiotic therapy, fecal microbiota transplantation, bone marrow chimeras, lung epithelium, interferon signature
- MeSH terms
- Fecal Microbiota Transplantation, RNA-Seq, Animals, Anti-Bacterial Agents, Bone Marrow Cells, Cell Line, Chimera, Epithelial Cells, Hematopoietic Stem Cells, Humans, Influenza, Human, Interferon Type I, Lung, Mice, Inbred C57BL, Influenza A virus, Gene Expression Regulation, Viral, Stromal Cells, Leukocyte Common Antigens, Mice, Knockout, Mice, Receptor, Interferon alpha-beta, Microbiota
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