Interferon-induced transmembrane protein 3 (IFITM3) limits lethality of SARS-CoV-2 in mice.
COVID-19
IFITM
IFITM3
SARS-CoV-2
interferon
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
05 04 2023
05 04 2023
Historique:
revised:
07
02
2023
received:
13
12
2022
accepted:
16
02
2023
medline:
6
4
2023
pubmed:
8
3
2023
entrez:
7
3
2023
Statut:
ppublish
Résumé
Interferon-induced transmembrane protein 3 (IFITM3) is an antiviral protein that alters cell membranes to block fusion of viruses. Conflicting reports identified opposing effects of IFITM3 on SARS-CoV-2 infection of cells, and its impact on viral pathogenesis in vivo remains unclear. Here, we show that IFITM3 knockout (KO) mice infected with SARS-CoV-2 experience extreme weight loss and lethality compared to mild infection in wild-type (WT) mice. KO mice have higher lung viral titers and increases in inflammatory cytokine levels, immune cell infiltration, and histopathology. Mechanistically, we observe disseminated viral antigen staining throughout the lung and pulmonary vasculature in KO mice, as well as increased heart infection, indicating that IFITM3 constrains dissemination of SARS-CoV-2. Global transcriptomic analysis of infected lungs shows upregulation of gene signatures associated with interferons, inflammation, and angiogenesis in KO versus WT animals, highlighting changes in lung gene expression programs that precede severe lung pathology and fatality. Our results establish IFITM3 KO mice as a new animal model for studying severe SARS-CoV-2 infection and overall demonstrate that IFITM3 is protective in SARS-CoV-2 infections in vivo.
Identifiants
pubmed: 36880581
doi: 10.15252/embr.202256660
pmc: PMC10074051
doi:
Substances chimiques
Interferons
9008-11-1
fragilis protein, mouse
0
Banques de données
GEO
['GSE194062']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e56660Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL168501
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI151230
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL154001
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI165391
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI130110
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157215
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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