Interferon‐induced transmembrane protein 3 (IFITM3) limits lethality of SARS‐CoV‐2 in mice

Abstract

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.

Innate immune control of influenza virus interspecies adaptation

“…Human IFITM3 deficiencies are associated with heightened severity of influenza, and data are emerging that IFITM3 deficiencies are a risk factor for severe COVID-19 [16][17][18][19][20] . Indeed, we and other groups have observed that Ifitm3 -/mice experience more severe influenza virus and SARS-CoV-2 infections, mimicking human IFITM3 defects 15,16,[21][22][23] .…”

“…Beneficial mutations that allow the virus to replicate more efficiently are enriched by outcompeting the parental virus and other mutants. Indeed, influenza virus and several other viruses replicate to higher titers in Ifitm3 -/versus WT mice 15,16,[21][22][23][32][33][34] , which represents a plausible mechanism for enhanced adaptation in these animals 31 . In our current study, mutations in the 2009 pandemic H1N1 virus passages that drive adaptation in mice were primarily observed in the viral polymerase subunits.…”

“…The amphipathic helix alters membrane curvature, lipid composition, and fluidity in a manner that disfavors virusto-cell membrane fusion, endowing IFITM3 with the ability to block release of virus genomes into the cytoplasm of cells [7][8][9][10][11][12] . As such, IFITM3 limits infection by a multitude of enveloped viruses in vitro, including influenza virus, Zika virus, and SARS-CoV-2 5,[13][14][15] . In humans, there are two deleterious single nucleotide polymorphisms (SNPs) in the IFITM3 gene that negatively impact its splicing or gene promoter efficacy [16][17][18] .…”

Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue

“…IFITM proteins provide constitutive and interferon-induced antiviral protection in many cell types by inhibiting the virus-cell membrane fusion step required for entry 47,48 . While it is established that murine IFITM3 restricts SARS-CoV-2 infection and limits viral disease in vivo 49,50 , the roles played by human IFITM proteins during SARS-CoV-2 infection have remained controversial. For example, it was demonstrated that IFITM proteins can inhibit SARS-CoV-2 infection in endosomes but can promote infection at the cell surface 51,52 .…”

Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation

“…Lungs were embedded in paraffin, sectioned, stained, and imaged by Histowiz (Histowiz.com, Brooklyn, NY, USA). Unbiased electronic quantification of resultant images was performed using ImageJ software and the color deconvolution method as described previously 9,[35][36][37] .…”