Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison
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Abstract
A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage 1,2. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.
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Impaired and delayed type I and type III IFN responses are associated with risk of severe COVID-19.
“Impaired and delayed type I and type III IFN responses are associated with risk of severe COVID-19 (Galani et al., 2021; Hadjadj et al., 2020).”
From Adaptive immunity to SARS-CoV-2 and COVID-19 (2021) · cites this paper as Galani et al., 2021
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- Authors
- Galani, I.-E., Rovina, N., Lampropoulou, V., Triantafyllia, V., Manioudaki, M., Pavlos, E., Koukaki, E., Fragkou, P. C., Panou, V., Rapti, V., Koltsida, O., Mentis, A., Koulouris, N., Tsiodras, S., Koutsoukou, A., & Andreakos, E.
- Affiliations
- Biomedical Research Foundation of the Academy of Athens (GR)
- National and Kapodistrian University of Athens (GR)
- Sotiria General Hospital (GR)
- Pasteur Hellenic Institute (GR)
- Corresponding author
- Andreakos, Evangelos
- ORCID
- Venue
- Nature Immunology
- Published
- 2020-12-04
- Volume
- 22
- Issue
- 1
- Pages
- 32-40
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W3107596380
- Cited by
- 503
- References
- 41
- Citations by year
- 2026: 22 · 2025: 46 · 2024: 58 · 2023: 91 · 2022: 156 · 2021: 128 · 2020: 1 · 2015: 1
- FWCI
- 32.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Immunology (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- EC | Horizon 2020 Framework Programme (779295, 767015)
- Janssen Pharmaceuticals
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- COVID-19 pandemic, SARS-CoV-2, influenza, type I interferon, interferon lambda, antiviral immunity, inflammatory cytokines, interleukin-6, TNF-α, interleukin-8, hyperinflammation, viral load, viral clearance, respiratory failure, mortality, blood transcriptome, cytokine dynamics
- MeSH terms
- COVID-19, SARS-CoV-2, Interferon Lambda, Humans, Immunity, Inflammation, Influenza, Human, Interferon Type I, Interferons, Length of Stay, Prognosis, Gene Expression, Cytokines, Disease Progression, Viral Load, Gene Expression Profiling
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