Deficiency of Tlr7 and Irf7 in mice increases the severity of COVID-19 through the reduced interferon production.
Animals
Toll-Like Receptor 7
/ genetics
Interferon Regulatory Factor-7
/ genetics
COVID-19
/ immunology
Mice
SARS-CoV-2
/ immunology
Lung
/ immunology
Mice, Knockout
Interferons
/ metabolism
Mice, Inbred C57BL
Severity of Illness Index
Viral Load
Membrane Glycoproteins
/ genetics
Disease Models, Animal
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
17 Sep 2024
17 Sep 2024
Historique:
received:
10
01
2024
accepted:
10
09
2024
medline:
18
9
2024
pubmed:
18
9
2024
entrez:
17
9
2024
Statut:
epublish
Résumé
Toll-like receptor 7 (Tlr7) deficiency-accelerated severe COVID-19 is associated with reduced production of interferons (IFNs). However, the underlying mechanisms remain elusive. To address these questions, we utilize Tlr7 and Irf7 deficiency mice, single-cell RNA analysis together with bone marrow transplantation approaches. We demonstrate that at the early phase of infection, SARS-CoV-2 causes the upregulation of Tlr7, Irf7, and IFN pathways in the lungs of the infected mice. The deficiency of Tlr7 and Irf7 globally and/or in immune cells in mice increases the severity of COVID-19 via impaired IFN activation in both immune and/or non-immune cells, leading to increased lung viral loads. These effects are associated with reduced IFN alpha and gamma levels in the circulation. The deficiency of Tlr7 tends to cause the reduced production and nuclear translocation of interferon regulatory factor 7 (IRF7) in the lungs of the infected mice, indicative of reduced IRF7 activation. Despite higher amounts of lung viral antigen, Tlr7 or Irf7 deficiency resulted in substantially reduced production of antibodies against SARS-CoV-2, thereby delaying the viral clearance. These results highlight the importance of the activation of TLR7 and IRF7 leading to IFN production on the development of innate and adaptive immunity against COVID-19.
Identifiants
pubmed: 39289468
doi: 10.1038/s42003-024-06872-5
pii: 10.1038/s42003-024-06872-5
doi:
Substances chimiques
Toll-Like Receptor 7
0
Interferon Regulatory Factor-7
0
Irf7 protein, mouse
0
Tlr7 protein, mouse
0
Interferons
9008-11-1
Membrane Glycoproteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1162Subventions
Organisme : U.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)
ID : P51OD011104-6
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)
ID : R01DK129881
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : R01HL165265
Organisme : NHLBI NIH HHS
ID : R35 HL139930
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Polatoğlu, I., Oncu-Oner, T., Dalman, I. & Ozdogan, S. COVID-19 in early 2023: Structure, replication mechanism, variants of SARS-CoV-2, diagnostic tests, and vaccine & drug development studies. MedComm (2020) 4, e228 (2023).
pubmed: 37041762
Carabelli, A. M. et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat. Rev. Microbiol. 21, 162–177 (2023).
pubmed: 36653446
pmcid: 9847462
Wang, C. et al. COVID-19 and influenza infections mediate distinct pulmonary cellular and transcriptomic changes. Commun. Biol. 6, 1265 (2023).
pubmed: 38092883
pmcid: 10719262
doi: 10.1038/s42003-023-05626-z
Beck, D. B. & Aksentijevich, I. Susceptibility to severe COVID-19. Science 370, 404–405 (2020).
pubmed: 33093097
doi: 10.1126/science.abe7591
Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 21, 133–146 (2023).
pubmed: 36639608
pmcid: 9839201
doi: 10.1038/s41579-022-00846-2
Hadjadj, J. et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369, 718–724 (2020).
pubmed: 32661059
pmcid: 7402632
doi: 10.1126/science.abc6027
Akamatsu, M. A., de Castro, J. T., Takano, C. Y. & Ho, P. L. Off balance: Interferons in COVID-19 lung infections. EBioMedicine 73, 103642 (2021).
pubmed: 34678609
pmcid: 8524139
doi: 10.1016/j.ebiom.2021.103642
Galbraith, M. D. et al. Specialized interferon action in COVID-19. Proc. Natl Acad. Sci. USA 119, e2116730119 (2022).
pubmed: 35217532
pmcid: 8931386
doi: 10.1073/pnas.2116730119
Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370, eabd4585 (2020).
pubmed: 32972996
pmcid: 7857397
doi: 10.1126/science.abd4585
Chauvineau-Grenier, A. et al. Autoantibodies neutralizing Type I interferons in 20% of COVID-19 deaths in a French Hospital. J. Clin. Immunol. 42, 459–470 (2022).
pubmed: 35083626
pmcid: 8791677
doi: 10.1007/s10875-021-01203-3
Reis, G. et al. Early treatment with pegylated Interferon Lambda for Covid-19. N. Engl. J. Med. 388, 518–528 (2023).
pubmed: 36780676
pmcid: 9933926
doi: 10.1056/NEJMoa2209760
Li, D. & Wu, M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther. 6, 291 (2021).
pubmed: 34344870
pmcid: 8333067
doi: 10.1038/s41392-021-00687-0
Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).
pubmed: 21616434
doi: 10.1016/j.immuni.2011.05.006
Blasius, A. L. & Beutler, B. Intracellular toll-like receptors. Immunity 32, 305–315 (2010).
pubmed: 20346772
doi: 10.1016/j.immuni.2010.03.012
Lim, K. H. & Staudt, L. M. Toll-like receptor signaling. Cold Spring Harb. Perspect. Biol. 5, a011247 (2013).
pubmed: 23284045
pmcid: 3579400
doi: 10.1101/cshperspect.a011247
Takagi, H. et al. Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of autoimmune inflammation. Sci. Rep. 6, 24477 (2016).
pubmed: 27075414
pmcid: 4830934
doi: 10.1038/srep24477
Duan, T., Du, Y., Xing, C., Wang, H. Y. & Wang, R. F. Toll-like receptor signaling and its role in cell-mediated immunity. Front. Immunol. 13, 812774 (2022).
pubmed: 35309296
pmcid: 8927970
doi: 10.3389/fimmu.2022.812774
van de Veerdonk, F. L. & Netea, M. G. Rare variants increase the risk of severe COVID-19. Elife 10, e67860 (2021).
pubmed: 33752797
pmcid: 7987329
doi: 10.7554/eLife.67860
van der Made, C. I. et al. Presence of genetic variants among young men with severe COVID-19. JAMA 324, 663–673 (2020).
pubmed: 32706371
doi: 10.1001/jama.2020.13719
Fallerini, C. et al. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study. Elife 10, e67569 (2021).
pubmed: 33650967
pmcid: 7987337
doi: 10.7554/eLife.67569
Asano, T. et al. X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19. Sci. Immunol. 6, eabl4348 (2021).
pubmed: 34413140
pmcid: 8532080
doi: 10.1126/sciimmunol.abl4348
Yin, Q. et al. A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2. Nat. Mater. 22, 380–390 (2023).
pubmed: 36717665
pmcid: 9981462
Chang, X. et al. TLR7 signaling shapes and maintains antibody diversity upon virus-like particle immunization. Front. Immunol. 12, 827256 (2021).
pubmed: 35126381
doi: 10.3389/fimmu.2021.827256
Miquel, C. H. et al. B cell-intrinsic TLR7 signaling is required for neutralizing antibody responses to SARS-CoV-2 and pathogen-like COVID-19 vaccines. Eur. J. Immunol. 53, e2350437 (2023).
pubmed: 37438976
doi: 10.1002/eji.202350437
Szeto, M. D. et al. Interferon and toll-like Receptor 7 Response in COVID-19: Implications of topical imiquimod for prophylaxis and treatment. Dermatology 237, 847–856 (2021).
pubmed: 34511591
doi: 10.1159/000518471
van der Sluis, R. M. et al. TLR2 and TLR7 mediate distinct immunopathological and antiviral plasmacytoid dendritic cell responses to SARS‐CoV‐2 infection. EMBO J. 41, e109622 (2022).
pubmed: 35178710
pmcid: 9108609
doi: 10.15252/embj.2021109622
Mantovani, S. et al. Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients. Genes Immun. 23, 51–56 (2022).
pubmed: 34952932
doi: 10.1038/s41435-021-00157-1
Wong, L.-Y. R. et al. Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19. Nature 605, 146–151 (2022).
pubmed: 35314834
pmcid: 9783543
doi: 10.1038/s41586-022-04630-3
Ellsworth, C. R. et al. Natural killer cells do not attenuate a mouse-adapted SARS-CoV-2-induced disease in Rag2(-/-) mice. Viruses 16, 611 (2024).
pubmed: 38675952
pmcid: 11054502
doi: 10.3390/v16040611
Jefferies, C. A. Regulating IRFs in IFN driven disease. Front. Immunol. 10, 325 (2019).
pubmed: 30984161
pmcid: 6449421
doi: 10.3389/fimmu.2019.00325
Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623–655 (2001).
pubmed: 11244049
doi: 10.1146/annurev.immunol.19.1.623
Negishi, H., Taniguchi, T. & Yanai, H. The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family. Cold Spring Harb. Perspect. Biol. 10, a028423 (2018).
pubmed: 28963109
pmcid: 6211389
doi: 10.1101/cshperspect.a028423
Qing, F. & Liu, Z. Interferon regulatory factor 7 in inflammation, cancer and infection. Front. Immunol. 14, 1190841 (2023).
pubmed: 37251373
pmcid: 10213216
doi: 10.3389/fimmu.2023.1190841
Ma, W., Huang, G., Wang, Z., Wang, L. & Gao, Q. IRF7: role and regulation in immunity and autoimmunity. Front. Immunol. 14, 1236923 (2023).
pubmed: 37638030
pmcid: 10449649
doi: 10.3389/fimmu.2023.1236923
Zhang, Q. et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 370, eabd4570 (2020).
pubmed: 32972995
pmcid: 7857407
doi: 10.1126/science.abd4570
Israelow, B. et al. Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling. J. Exp. Med. 217, e20201241 (2020).
pubmed: 32750141
pmcid: 7401025
doi: 10.1084/jem.20201241
Sokal, A. et al. Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination. J. Exp. Med. 220, e20220258 (2023).
pubmed: 36342455
doi: 10.1084/jem.20220258
Lind, N. A., Rael, V. E., Pestal, K., Liu, B. & Barton, G. M. Regulation of the nucleic acid-sensing Toll-like receptors. Nat. Rev. Immunol. 22, 224–235 (2022).
pubmed: 34272507
doi: 10.1038/s41577-021-00577-0
Sun, H. et al. Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives. Biomark. Res. 10, 89 (2022).
pubmed: 36476317
pmcid: 9727882
doi: 10.1186/s40364-022-00436-7
McCray, P. B. Jr. et al. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J. Virol. 81, 813–821 (2007).
pubmed: 17079315
doi: 10.1128/JVI.02012-06
Qin, Z. et al. Endothelial cell infection and dysfunction, immune activation in severe COVID-19. Theranostics 11, 8076–8091 (2021).
pubmed: 34335981
pmcid: 8315069
doi: 10.7150/thno.61810
Bortz, R. H. et al. Single-Dilution COVID-19 Antibody test with qualitative and quantitative readouts. mSphere 6, https://doi.org/10.1128/msphere.00224-00221 (2021).
Vu Van, D. et al. Local T/B cooperation in inflamed tissues is supported by T follicular helper-like cells. Nat. Commun. 7, 10875 (2016).
doi: 10.1038/ncomms10875
Cicalese, M. P., Salek-Ardakani, S. & Fousteri, G. Editorial: Follicular helper T cells in immunity and autoimmunity. Front. Immunol. 11, 1042 (2020).
pubmed: 32670272
pmcid: 7326138
doi: 10.3389/fimmu.2020.01042
El-Hefnawy, S. M. et al. COVID-19 susceptibility, severity, clinical outcome and Toll-like receptor (7) mRNA expression driven by TLR7 gene polymorphism (rs3853839) in middle-aged individuals without previous comorbidities. Gene Rep. 27, 101612 (2022).
pubmed: 35463461
pmcid: 9013694
doi: 10.1016/j.genrep.2022.101612
Solanich, X. et al. Genetic screening for TLR7 variants in young and previously healthy men with severe COVID-19. Front. Immunol. 12, 719115 (2021).
pubmed: 34367187
pmcid: 8343010
doi: 10.3389/fimmu.2021.719115
Spiering, A. E. & de Vries, T. J. Why females do better: The X Chromosomal TLR7 gene-dose effect in COVID-19. Front. Immunol. 12, 756262 (2021).
pubmed: 34858409
pmcid: 8632002
doi: 10.3389/fimmu.2021.756262
Ning, S., Pagano, J. S. & Barber, G. N. IRF7: activation, regulation, modification and function. Genes Immun. 12, 399–414 (2011).
pubmed: 21490621
pmcid: 4437765
doi: 10.1038/gene.2011.21
Liang, Q., Deng, H., Sun, C. W., Townes, T. M. & Zhu, F. Negative regulation of IRF7 activation by activating transcription factor 4 suggests a cross-regulation between the IFN responses and the cellular integrated stress responses. J. Immunol. 186, 1001–1010 (2011).
pubmed: 21148039
doi: 10.4049/jimmunol.1002240
Kim, T. K., Kim, T., Kim, T. Y., Lee, W. G. & Yim, J. Chemotherapeutic DNA-damaging drugs activate Interferon Regulatory Factor-7 by the Mitogen-activated Protein Kinase Kinase-4-c-Jun NH2-Terminal Kinase Pathway1. Cancer Res. 60, 1153–1156 (2000).
pubmed: 10728664
Crotty, S. T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529–542 (2014).
pubmed: 25367570
pmcid: 4223692
doi: 10.1016/j.immuni.2014.10.004
Collins, M., Ling, V. & Carreno, B. M. The B7 family of immune-regulatory ligands. Genome Biol. 6, 223 (2005).
pubmed: 15960813
pmcid: 1175965
doi: 10.1186/gb-2005-6-6-223
Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).
pubmed: 15454922
doi: 10.1038/ni1112
Feng, D. et al. Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration. J. Clin. Invest. 126, 2321–2333 (2016).
pubmed: 27159394
pmcid: 4887171
doi: 10.1172/JCI84921
Hu, W. et al. Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin. Nat. Med. 14, 98–103 (2008).
pubmed: 18157141
doi: 10.1038/nm1674
Liu, F. et al. Versatile cell ablation tools and their applications to study loss of cell functions. Cell Mol. Life Sci. 76, 4725–4743 (2019).
pubmed: 31359086
pmcid: 6858955
doi: 10.1007/s00018-019-03243-w
Liu, F. et al. Distinct fate, dynamics and niches of renal macrophages of bone marrow or embryonic origins. Nat. Commun. 11, 2280 (2020).
pubmed: 32385245
pmcid: 7210253
doi: 10.1038/s41467-020-16158-z