SARS-CoV-2 Variants of Concern Hijack IFITM2 for Efficient Replication in Human Lung Cells

Nchioua, Rayhane; Schundner, Annika; Kmieć, Dorota; Bozzo, Caterina Prelli; Zech, Fabian; Koepke, Lennart; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Frick, Manfred; Kirchhoff, Frank

doi:10.1128/jvi.00594-22

Cited by 29 publications

(27 citation statements)

References 75 publications

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“…Having shown that GBPs interfere with SARS-CoV-2 spike cleavage, we sought to test whether this may sensitize SARS-CoV-2 to IFITM-mediated inhibition. IFITMs are another family of spike-targeting interferon-inducible restriction factors that can inhibit infection of a range of viruses, including SARS-CoV-2 ( 7 , 12 , 21 – 24 , 41 ), by perturbing viral fusion with host cell membranes and thus inhibiting infection of target cells. IFITMs are differentially localized in cells with IFITM1 being found mostly at the plasma membrane and IFITM2/3 predominantly endosomal.…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 evolution influences GBP and IFITM sensitivity

Mesner

Reuschl

Whelan

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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SARS-CoV-2 spike requires proteolytic processing for viral entry. A polybasic furin-cleavage site (FCS) in spike, and evolution toward an optimized FCS by dominant variants of concern (VOCs), are linked to enhanced infectivity and transmission. Here we show interferon-inducible restriction factors Guanylate-binding proteins (GBP) 2 and 5 interfere with furin-mediated spike cleavage and inhibit the infectivity of early-lineage isolates Wuhan-Hu-1 and VIC. By contrast, VOCs Alpha and Delta escape restriction by GBP2/5 that we map to the spike substitution D614G present in these VOCs. Despite inhibition of spike cleavage, these viruses remained sensitive to plasma membrane IFITM1, but not endosomal IFITM2 and 3, consistent with a preference for TMPRSS2-dependent plasma membrane entry. Strikingly, we find that Omicron is unique among VOCs, being sensitive to restriction factors GBP2/5, and also IFITM1, 2, and 3. Using chimeric spike mutants, we map the Omicron phenotype and show that the S1 domain determines Omicron’s sensitivity to GBP2/5, whereas the S2’ domain determines its sensitivity to endosomal IFITM2/3 and preferential use of TMPRSS2-independent entry. We propose that evolution of SARS-CoV-2 for the D614G substitution has allowed for escape from GBP restriction factors, but the selective pressures on Omicron for spike changes that mediate antibody escape, and altered tropism, have come at the expense of increased sensitivity to innate immune restriction factors that target virus entry.

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Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 evolution influences GBP and IFITM sensitivity

Mesner

Reuschl

Whelan

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…The exact effect of IFITM proteins during SARS-CoV-2 replication is contentious, with some studies showing that IFITM proteins inhibit cellular entry of SARS-CoV-2, in a similar manner to influenza 19 , 76 , 134 , 142 , whereas others suggest that in some contexts they enhance infection, in a manner similar to that described for OC43 and HKU1 (refs. 76 , 134 , 143 – 145 ). The exact role of IFITM proteins is likely to be context specific, such as the particular entry pathway used by a particular virus in a given cell type or cell line, the use of live virus versus pseudovirus and the level of IFITM protein expressed.…”

Section: Innate Immunity and Sars-cov-2 Variantsmentioning

confidence: 99%

“…Several VOCs have been shown to have different degrees of sensitivity to IFITM protein inhibition or enhancement, quite often associated with specific entry pathways or furin cleavage phenotypes. For example, Omicron, which is more efficient at endosomal entry than early variants and other VOCs, appears to show greater inhibition (or in some cases enhancement) by endosomal IFITM proteins, although this does appear to be highly dependent on the cell system used 32 , 76 , 145 . This is possibly due to Omicron either having to compromise innate evasion due to adaptive immunity avoidance, particularly in the context of vaccine-induced spike antibodies, or having to adapt to use IFITM proteins as cofactors for entry.…”

Section: Innate Immunity and Sars-cov-2 Variantsmentioning

confidence: 99%

SARS-CoV-2 variant biology: immune escape, transmission and fitness

et al. 2023

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In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed ‘variants of concern’ (VOCs). Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19.

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“…However, we (almost) know with certainty that angiotensin-converting enzyme 2 (ACE2) is a crucial cell entry site for the spike (S) protein of SARS-CoV-2, and due to the high expression of ACE2 in mammalian cells, the virus can easily cause damage to multiple organs [ 11 , 12 ]. However, many other additional host factors may affect the efficacy and play roles in the COVID-19 pathogenesis, such as auxiliary SARS-CoV-2 receptors (heparan sulfate, Scavenger receptor class B member 1, neuropilin-1), alternatives to ACE2 receptors (e.g., cell surface proteins, tyrosine-protein kinase receptor UFO, low-density lipoprotein receptor class A domain-containing protein 3, C-type lectin domain family 4 member G, interferon-inducible transmembrane proteins), host proteases that mediate the viral entry via the spike (S) protein, priming–transmembrane serine protease 2 (TMPRSS2), transmembrane glycoprotein CD147, members of the phosphatidylinositol 3-kinase (PI3K) pathway, some transcriptional factors, and histone-modifying enzymes [ 13 , 14 , 15 ]. Lysosomal cysteine protease cathepsin L was also found to be a key factor in SARS-CoV-2 infection and a promising therapeutic target [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Induced Pluripotent Stem Cell-Derived Organoids: Their Implication in COVID-19 Modeling

Csöbönyeiová

Klein

Kuniaková

et al. 2023

IJMS

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The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant global health issue. This novel virus’s high morbidity and mortality rates have prompted the scientific community to quickly find the best COVID-19 model to investigate all pathological processes underlining its activity and, more importantly, search for optimal drug therapy with minimal toxicity risk. The gold standard in disease modeling involves animal and monolayer culture models; however, these models do not fully reflect the response to human tissues affected by the virus. However, more physiological 3D in vitro culture models, such as spheroids and organoids derived from induced pluripotent stem cells (iPSCs), could serve as promising alternatives. Different iPSC-derived organoids, such as lung, cardiac, brain, intestinal, kidney, liver, nasal, retinal, skin, and pancreatic organoids, have already shown immense potential in COVID-19 modeling. In the present comprehensive review article, we summarize the current knowledge on COVID-19 modeling and drug screening using selected iPSC-derived 3D culture models, including lung, brain, intestinal, cardiac, blood vessels, liver, kidney, and inner ear organoids. Undoubtedly, according to reviewed studies, organoids are the state-of-the-art approach to COVID-19 modeling.

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SARS-CoV-2 Variants of Concern Hijack IFITM2 for Efficient Replication in Human Lung Cells

Abstract: Recent data indicate that SARS-CoV-2 requires endogenously expressed IFITM proteins for efficient infection. However, the results were obtained with an early SARS-CoV-2 isolate.

Cited by 29 publications

References 75 publications

SARS-CoV-2 evolution influences GBP and IFITM sensitivity

SARS-CoV-2 evolution influences GBP and IFITM sensitivity

SARS-CoV-2 variant biology: immune escape, transmission and fitness

Induced Pluripotent Stem Cell-Derived Organoids: Their Implication in COVID-19 Modeling

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