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. Author manuscript; available in PMC: 2025 May 24.
Published in final edited form as: Curr Opin Immunol. 2024 May 24;87:102426. doi: 10.1016/j.coi.2024.102426

The Antiviral State of the Cell: lessons from SARS-CoV-2

Jérémie Le Pen 1, Charles M Rice 1
PMCID: PMC11260430  NIHMSID: NIHMS1998886  PMID: 38795501

Abstract

In this review, we provide an overview of the intricate host-virus interactions that have emerged from the study of SARS-CoV-2 infection. We focus on the antiviral mechanisms of interferon-stimulated genes (ISGs) and their modulation of viral entry, replication, and release. We explore the role of a selection ISGs, including BST2, CD74, CH25H, DAXX, IFI6, IFITM1–3, LY6E, NCOA7, PLSCR1, OAS1, RTP4 and ZC3HAV1/ZAP, in restricting SARS-CoV-2 infection and discuss the virus’s countermeasures. By synthesizing the latest research on SARS-CoV-2 and host antiviral responses, this review aims to provide a deeper understanding of the antiviral state of the cell under SARS-CoV-2 and other viral infections, offering insights for the development of novel antiviral strategies and therapeutics.

Keywords: Antiviral state of the cell, innate immunity, Intrinsic immunity, interferon, interferonstimulated genes, Virus, Coronavirus, SARS-CoV-2, COVID-19, virus-host interactions

Graphical abstract

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Introduction

Innate immunity provides a rapid response to viral infections, independent of prior exposure to a specific virus [1,2]. Innate immunity generally encompasses both intrinsic immunity, featuring constitutively expressed antiviral effectors, and induced innate immunity, which is activated by infection [3]. Host cells detect viral infections by sensing pathogen-associated molecular patterns (PAMPs) through host pattern recognition receptors (PRRs) [1]. In jawed vertebrates, PRR activation triggers the production of interferons (IFNs), a family of cytokines that act in both autocrine and paracrine manners to induce an antiviral state in infected and neighboring cells [2]. The antiviral state is a cellular condition in which the cell is primed to defend itself against viral infections through the IFN-mediated expression of numerous genes known as interferon-stimulated genes (ISGs) [4,5].

In recent reviews in Current Opinion in Immunology, Liu and Gack discussed the induction of, and evasion strategies from the IFN response by SARS-CoV-2 [1], while Bastard et al. explored how defects in IFN production and signaling contribute to severe COVID-19 [2]. These reviews highlighted the importance of the IFN response in antiviral defense. Here, we discuss how ISGs establish an antiviral state within the cell, primarily focusing on SARS-CoV-2 infection.

ISG induction by type I and type III IFNs

Human IFNs are classified into three main categories – type I, type II, and type III – based on their cell surface receptor usage and biological functions. Type I and type III IFNs are key in inducing the antiviral state of the cell, notably during SARS-CoV-2 infection [6].

Upon binding of type I and type III IFNs to their respective receptors, the shared JAK-STAT signaling pathway is activated, that will lead to the induction of hundreds of ISG and repression of some IFN-repressed genes [7–9]. In addition to the canonical JAK-STAT pathway, type I and type III IFNs can signal through non-canonical pathways that induce specific ISG subsets [10–13].

Despite sharing downstream signaling components and activating mainly overlapping sets of ISGs, there are some differences between type I and type III IFNs:

  1. Anatomical sites: Type I IFNs, including the α and β subtypes, are produced by various cell types and signal through the widely expressed receptor IFNAR. Type III IFNs (IFN-λ1–4) are mainly produced at barrier surfaces, such as the respiratory and gastrointestinal tracts, with their receptor primarily located on epithelial cells and a specific subset of immune cells. IFN-λ1 and IFN-λ3, but not IFN-λ2 or IFN-I, were shown to elicit a protective antiviral state in the upper airways of COVID-19 patients [14].

  2. Kinetics and magnitude: Type I IFNs induces a faster and more potent response, whereas type III IFNs induces a more prolonged response with lower overall magnitude [15].

  3. Tissue damage: Type III IFN is generally less inflammatory than type I IFN [13,16]. Nonetheless, excessive production of either type I or type III IFNs can lead to damage of host tissues [14,17,18].

Given these differences, current research is focusing on type III IFN as a potential prophylaxis or treatment for COVID-19 [19].

It is however important to remember that nature is not bound by these classifications and future studies may uncover new receptor usage and biological functions for the different IFN types in different contexts.

Methods to study antiviral ISG functions

ISGs can generally be classified into regulatory ISGs, which exert either positive or negative feedback on the immune response, and effector ISGs that have a direct antiviral effect, impairing various steps of the viral replication cycle [4,5,20].

Studying individual effector ISG activities can be challenging due to functional redundancies. Overexpression assays (OE) have proven effective, entailing the individual OE of ISGs using either cDNA ectopic expression [21] or CRISPR activation at endogenous loci [22] in cells lacking an IFN response during viral infection. Virus susceptibility is then assessed.

While OE screens possess notable strengths, they may exhibit bias towards ISGs capable of acting autonomously when individually overexpressed, without needing the complete cellular context of the IFN-induced antiviral state. Moreover, they may be biased towards regulatory ISGs that engage larger gene networks, such as interferon regulatory transcription factors (IRFs) and PRRs. Additionally, OE can be somewhat artificial. An alternative approach is ISG loss-of-function assays (LOF), followed by IFN treatment and then virus infection [23–26]. Although the LOF approach is challenging due to functional redundancies among ISGs, it may help identify ISGs that are relevant when expressed at a physiological level.

Selected human ISGs influencing SARS-CoV-2 infection

In this section, we examine the role of selected ISGs found in OE or LOF screens with SARS-CoV-2 infection (Figure 1). Owing to space constraints, not all ISGs known to influence SARS-CoV-2 infection are covered. Key ISGs are used as representatives to explore their roles across various stages of SARS-Cov-2 infection.

Figure 1. Selected human ISGs influencing the SARS-CoV-2 replication cycle.

Figure 1.

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Not all ISGs influencing SARS-CoV-2 infection are included in this diagram.

ISGs restricting SARS-CoV-2 entry: CD74 restricts virus-cell membrane fusion by inhibiting the processing of viral structural proteins by endolysosomal cathepsins [20,27]. CH25H facilitates cholesterol sequestration from the ER membrane to lipid droplets via ACAT, which indirectly leads to a decrease in cholesterol at the endosomal and plasma membranes. This decrease in cholesterol level impedes virus-cell membrane fusion and viral entry [28,29]. LY6E and PLSCR1 impede virus-cell membrane fusion via currently undetermined mechanisms [25,26,30]. NCOA7 increases lysosome acidification, leading to viral antigen degradation by lysosomal proteases [31,32].

ISGs restricting SARS-CoV-2 post-entry: DAXX translocates from the nucleus to the sites of SARS-CoV-2 replication during infection, where it likely restricts it [23]. SARS-CoV-2 papain-like protease (PLpro), part of the nsp3 protein, degrades DAXX as an evasion mechanism to counteract host antiviral responses [23]. IFI6 normally localizes to the ER [24]. It restricts SARS-CoV- 2 via currently undetermined mechanisms [23,26,33]. RTP4 binds to the the viral genomic RNA, inhibiting its replication [33,34]. OAS1 detects viral double-stranded RNA and activates RNase L [22,33,35–40].

ISGs restricting SARS-CoV-2 exit: BST2 blocks virus release by tethering the virion to the cell membrane [41]. SARS-CoV- 2 proteins ORF7a and spike impair BST2’s antiviral function [41–43].

ISGs with dual roles in SARS-CoV-2 infection: IFITM1,2,3 are known to modulate virus-cell membrane fusion; however, their influence in SARS-CoV-2 infection remains debated, with both proviral and antiviral effects reported [44–53]. ZC3HAV1/ZAP impairs SARS-CoV-2 protein production by inhibiting programmed ribosomal frameshifting (antiviral effect) [54,55], yet it also facilitates the creation of ER-derived double-membrane vesicles essential for SARS-CoV-2 replication (proviral effect) [26,56].

ISGs restricting SARS-CoV-2 entry

SARS-CoV-2 enters host cells primarily through two routes:

  1. Endocytosis. The virus binds to its receptor, angiotensin-converting enzyme 2 (ACE2), at the cell surface, and is then internalized through endocytic vesicles. Low pH in endosomes triggers fusion between viral and endosomal membranes, releasing the viral genome into the cytosol.

  2. Fusion at or near the cell surface. The viral spike protein binds to ACE2 and is cleaved by host proteases, such as transmembrane serine protease 2 (TMPRSS2), enabling direct fusion of the viral envelope with the host cell plasma membrane, allowing the viral genome to enter the cell [57].

ISGs play a crucial role in blocking SARS-CoV-2 entry:

Cholesterol 25-hydroxylase (CH25H) encodes an enzyme that converts cholesterol into 25-hydroxycholesterol (25HC), exhibiting broad-spectrum activity against enveloped viruses [4,58]. Both CH25H OE and 25HC treatment restrict SARS-CoV-2 in Calu-3, HEK293-hACE2, and HEK293-hACE2-TMPRSS2 cells [28,29]. Mice infected with mouse-adapted SARS-CoV-2 exhibited significantly reduced viral loads when treated with 25HC [59]. Two studies support a model in which 25HC reduces cholesterol levels in the endosomal and plasma membranes, effectively inhibiting virus-cell membrane fusion in both SARS-CoV-2 entry routes [28,29]. Wang et al. propose that the mechanism involves the activation of the enzyme acyl-CoA:cholesterol acyltransferase (ACAT), leading to the sequestration of accessible cholesterol in lipid droplets [29]. This underlines the importance of cholesterol in virus–cell membrane fusion processes. CH25H may restrict different viruses through various mechanisms [4].

The short isoform of Nuclear Receptor Coactivator 7 (NCOA7), which is induced by IFN, encodes another broad-spectrum antiviral protein that inhibits endocytic virus entry [20]. NCOA7 effectively restricted SARS-CoV-2 in two ISG OE screens [22,33]. In the proposed mechanism, NCOA7 restricts SARS-CoV-2 endocytic entry by directly interacting with vacuolar H+-ATPase (V-ATPase), resulting in abnormal vesicle acidification and lysosomal protease activation [31,32]. Interestingly, TMPRSS2 OE reduces the antiviral effects of NCOA7 by promoting the pH-independent plasma membrane fusion entry route. This suggests that SARS-CoV-2 may have evolved the TMPRSS2-mediated entry mechanism to evade restriction by NCOA7 [32].

Phospholipid scramblase 1 (PLSCR1) has been described as either a regulatory or an effector ISG, depending on the context. An early study found that PLSCR1 restricts encephalomyocarditis virus and vesicular stomatitis virus in human ovarian carcinoma Hey1B cells by potentiating the IFN-mediated induction of ISGs [60]. Recently, PLSCR1 was identified as a SARS-CoV-2 antiviral in two LOF screens [25,26]. In addition, a human genetics study suggested that PLSCR1 could have a modest but statistically significant impact on COVID-19 outcomes in patients [61,62]. Subsequent studies found PLSCR1 directly blocks SARS-CoV-2 entry, instead of potentiating ISG induction, in A549-ACE2 and Huh-7.5 cells [25,26]. Interestingly, basal levels of intrinsic PLSCR1 alone are sufficient to restrict SARS-CoV-2, independent of IFN signaling. However, recent SARS-CoV-2 variants such as Omicron (BA.5) are less susceptible to PLSCR1 restriction, indicating that SARS-CoV-2 may currently be adapting to PLSCR1-mediated restriction [26].

Lymphocyte antigen 6 complex locus E (LY6E) is an example of an ISG that exhibits antiviral or proviral effects depending on the virus and context. Recently, LY6E was found to restrict SARS-CoV-2 and other coronaviruses in five OE screens [22,33,41,63,64] and two LOF screens [23,25]. LY6E inhibited virus-cell membrane fusion via a yet-to-be-determined mechanism [30]. Ly6e KO led to increased viral pathogenesis in mice infected with the murine coronavirus (mouse hepatitis virus [MHV]), or the SARS-CoV-2 Gamma variant, which can replicate in the murine respiratory tract. This outcome was, in part, attributed to the loss of constitutive LY6E, which is believed to protect certain immune cells, including B cells and respiratory tract secretory cells from infection [65]. Indeed, despite being an ISG, LY6E is constitutively expressed in numerous tissues without IFN stimulation [66,67]. Prior to its identification as a SARS-CoV-2 antiviral, LY6E OE had been shown to enhance infection by multiple viruses including IAV, flaviviruses and some togaviruses in cell culture [21,66]. Detailed examination revealed that LY6E facilitates IAV entry by promoting capsid uncoating after endosomal escape via a yet-to-be-determined mechanism. The overall effect could be context dependent. On the one hand, LY6E is beneficial to IAV infection in cell culture. However, in vivo, LY6E-mediated IAV uptake may accelerate immune activation, benefiting the host [66]. This highlights the challenge in categorizing a host factor as either “proviral” or “antiviral,” as this classification often depends on the context.

ISGs restricting SARS-CoV-2 post-entry

Death domain-associated protein (DAXX) is another ubiquitously expressed protein whose expression is enhanced by IFN. Primarily located in the nucleus, DAXX represses transcription of certain DNA viruses like HCMV [68]. DAXX also exhibits cytoplasmic antiviral functions; it hinders human immunodeficiency virus type 1 (HIV-1) uncoating, possibly by increasing the stability of viral RNA containing capsids [69]. A recent study conducted a LOF ISG screen, in which A549-ACE2 cells with CRISPR KOs for a subset of ISGs were pre-treated with IFN-α before SARS-CoV-2 infection. SARS-CoV-2 positive cells were then isolated by fluorescence activated cell sorting (FACS). The researchers noted an enrichment for DAXX KO cells in this population and further uncovered a subtle yet significant role for DAXX in restricting SARS-CoV-2 [23]. DAXX relocates from the nucleus to sites of viral replication in the cytoplasm, where it restricts SARS-CoV-2 using mechanisms that are not yet fully understood. Interestingly, although DAXX is an ISG in some contexts, its mRNA expression was not significantly increased by IFN treatment in the A549-ACE2 cells used in this study (protein levels were not examined). An intrinsic and IFN-independent fraction of DAXX may be sufficient to partially restrict SARS-CoV-2. The SARS-CoV-2 papain-like protease, encoded by Nsp3, triggers the proteasomal degradation of DAXX, suggesting that the virus has evolved to partially evade DAXX-mediated restriction [23].

Interferon alpha inducible protein 6 (IFI6) restricted SARS-CoV-2 in two LOF screens conducted on cells pretreated with IFN [23,26]. IFI6 is located in the endoplasmic reticulum (ER) and has previously been shown to suppress flaviviruses by hindering the formation of replication organelles [24]. These organelles, invaginations of the ER membrane induced by flaviviruses, are essential for viral genome replication and shielding against cytosolic factors such as PRRs. Human coronaviruses (hCoVs) utilize replication organelles that are also derived from the ER but face outwards towards the cytoplasm, named double-membrane vesicles (DMVs). Further research is needed to determine if IFI6 prevents SARS-CoV-2 DMV formation or operates through different mechanisms. How does IFI6 LOF reduce the antiviral effects of the IFN response against flaviviruses and SARS-CoV-2, given that IFI6 is an effector ISG not involved in IFN signaling [24] and other effector ISGs may be functionally redundant? IFI6 could potentially coordinate the combined action of multiple other ISG products at the ER. Furthermore, a recent study suggests that IFI6 also acts as a negative regulator of the PRR retinoic acid-inducible gene-I (RIG-I) activation [70], which occurs upstream of IFN production. Therefore, IFI6 may limit the production of IFN while enhancing its antiviral effects.

ISGs regulating innate immunity and restricting SARS-CoV-2 replication

The 2’−5’-oligoadenylate synthetases OAS1, OAS2 and OAS3 produce 2’−5’-oligoadenylate (2–5A) when sensing cytosolic viral double-stranded RNA (dsRNA). 2–5A activates the latent endoribonuclease (RNase L), which subsequently degrades both viral and cellular RNAs. This process can lead to apoptosis or generate PAMPs that enhance the immune response. Several known coronaviruses, including human Middle East respiratory syndrome coronavirus (MERS-CoV), have evolved 2’,5’-phosphodiesterases (PDEs) that prevent 2–5A accumulation and block the activation of the OAS-RNase L pathway [71,72]. SARS-CoV-2 activated the OAS-RNase L pathway in Calu-3 and A549-ACE2 cells, an effect not observed with WT MERS-CoV but seen with MERS-CoV lacking NS4ab, which includes the PDE. This suggests that SARS-CoV-2 may lack the PDE necessary to evade this antiviral pathway [35]. OAS1 has two main isoforms: the prenylated, perinuclear p46 isoform, and the cytoplasmic p42 isoform. OAS1 OE restricted SARS-CoV-2 in two independent ISG OE screens [22,33], but it remains debated whether this antiviral function is specific to p46 or shared with p42 [22,33,39,73,74]. The locus encoding OAS1–3 has been linked to susceptibility to severe COVID-19 in several human genetic studies [36–38]. Further genetic analysis revealed that a common genetic haplotype comprising two OAS1 single nucleotide polymorphisms is associated with a higher risk of severe COVID-19. These two variants, one affecting splicing and the other causing a missense mutation, influence OAS1 expression [39,40]. In summary, these findings support a model in which OAS1 levels can vary between individuals, and higher levels of OAS1 offer increased protection against SARS-CoV-2 infection. Interestingly, OAS2 and OAS3 do not appear to be redundant with OAS1, possibly indicating OAS1–3 specificity, with OAS1 being more effective at binding SARS-CoV-2 dsRNA. Lastly, rare biallelic loss-of-function mutations in the OAS-RNase L pathway have been identified as a cause of multisystem inflammatory syndrome in children, a rare and severe condition characterized by abnormally high production of inflammatory cytokines that occurs following asymptomatic or mild COVID-19 [75]. The IFN-induced OAS-RNase L pathway is therefore capable of regulating inflammation through a mechanism that has yet to be fully elucidated.

ISGs restricting SARS-CoV-2 exit

Bone marrow stromal antigen 2 (BST2), also known as tetherin, was initially discovered for its ability to prevent the cellular release of HIV-1 virions [76–78]. BST2 encodes a protein that spans both the viral and host cell membranes, attaching them together. An ISG OE screen revealed that BST2 restricts SARS-CoV-2 virion release in 293T-ACE2 and Huh7 cells [41]. Interestingly, the SARS-CoV-2 proteins ORF7a and spike directly interact with BST2, altering its cellular localization and quantities, respectively. These interactions allow for partial evasion from BST2’s restriction [41–43].

ISGs with dual roles in SARS-CoV-2 infection

Interferon induced transmembrane protein 3 (IFITM3) was identified as an antiviral effector in a whole-genome siRNA screen for genes that influence IAV infection [79]. A polymorphism in the IFITM3 promoter was found to be associated with decreased binding of IFR3, lower IFITM3 mRNA levels, and increased risk of severe influenza [80]. IFITM3 interferes with IAV’s endocytic entry into cells by altering the lipid composition at the contact site between the virus and endosomal membranes. This modification makes it difficult for the virus to be released into the cytoplasm [81–84]. Subsequently, virus-containing endosomes are directed to lysosomes for degradation [81,85]. IFITM1 and IFITM2, along with IFITM3, restrict many enveloped viruses [79,86]. However, the situation appears more complex for coronaviruses, as an early report suggested that IFITM3 OE facilitates entry of HCoV-OC43 [44]. Two consecutive studies by the same group showed that (i) IFITM2 restricts wild-type SARS-CoV-2 endosomal entry in A549-ACE2 cells [45], and (ii) the Alpha variant of SARS-CoV-2 has a spike protein mutation that enables non-endosomal entry at the plasma membrane, bypassing this restriction [46]. An independent group found that all IFITM1–3s inhibited SARS-CoV-2 infection when overexpressed in HEK293T-ACE2 cells. A mutation in IFITM3 that changes its localization from endosomes to the plasma membrane was found to convert IFITM3 from a restriction factor to an enhancer of SARS-CoV-2 infection when overexpressed in HEK293T-ACE2 or HEK293T-ACE2-TMPRSS2 cells [47]. A third group made the surprising observation that siRNA-mediated silencing of IFITM1–3 in Calu-3 cells and primary small airway epithelial cells associated with strongly reduced levels of SARS-CoV-2 RNA production in the presence of IFN-β. In accordance, treatment with IFITM-derived peptides or IFITM-targeting antibodies decreased viral N protein expression and cytopathic effects in gut organoids. This data thus suggests a proviral function for IFITM1–3 [48]. The impact of IFITMs on SARS-CoV-2 entry may vary depending on factors such as entry route, cell types, virus strain, and other variables [46–52]. This raises the question of whether IFITMs primarily benefit the host or SARS-CoV-2 in vivo. A recent study suggests the former, as IFITM3 KO mice exhibit hyper susceptibility to both the mouse-adapted MA10 SARS-CoV-2 strain and the human-isolated WA1/2020 SARS-CoV-2 strain [53].

Zinc-finger antiviral protein (ZC3HAV1/ZAP) was initially identified as an antiviral factor that binds the SARS-CoV-2 RNA genome [54] and prevents programmed ribosomal frameshifting [55]. However, a recent LOF screen revealed that ZC3HAV1/ZAP may also exhibit proviral activity [26]. This could be attributed to ZC3HAV1/ZAP’s role in facilitating the formation of DMVs [56]. It remains unclear whether the pro- or antiviral roles of ZC3HAV1/ZAP are dependent on cellular context or isoforms.

Conclusions

The IFN pathway is crucial for controlling viruses in cell culture and in vivo [1,2]. Despite SARS-CoV-2’s ongoing adaptation to the human innate immune system [87,88], the constitutive expression of specific antiviral ISG effectors, along with the rapid engagement of the antiviral state in cells receiving IFN before the infection front, may limit the virus’s evasion strategies. The complexity of the cellular antiviral state is only beginning to be unraveled, with key questions remaining:

  1. Many ISGs show a basal level of expression, even without IFN signaling. Do these intrinsic ISGs play a role in cellular functions beyond antiviral responses?

  2. Can individual effector ISGs influence the outcome of viral infections in patients, despite the redundancies within the immune system?

  3. What are the combinatorial effects of different ISGs in antiviral defense?

  4. How do ISGs contribute to the full breadth of the immune response, orchestrating the different specialized immune cells at the site of infection?

  5. Can ISG-driven antiviral mechanisms inform the design of new antiviral therapeutics?

Highlights.

  • Interferon-stimulated genes (ISGs) play a crucial role in establishing an antiviral state within the cell.

  • The ISG products CD74, BST2, CH25H, DAXX, IFI6, LY6E, NCOA7, PLSCR1, OAS1 and RTP4 utilize diverse mechanisms to restrict SARS-CoV-2 entry, replication, and release.

  • Some ISGs, such as DAXX, LY6E, and PLSCR1, have intrinsic antiviral functions independently of IFN.

  • The roles of the ISGs IFITM1,2,3 and ZC3HAV1/ZAP in SARS-CoV-2 infection remain under discussion, with both proviral and antiviral effects reported.

  • SARS-CoV-2 proteins, including nsp3, ORF7a, and spike, have evolved to evade or counteract antiviral ISGs, demonstrating the dynamic nature of virus-host interactions.

Acknowledgements

We would like to express our gratitude to those who read and offered valuable suggestions for this review, including Danyel Lee, Inna Ricardo-Lax, William M. Schneider, and John W. Schoggins. The Laboratory of Virology and Infectious Disease was supported in part by the NIH (R01AI091707–10 to C.M.R.). J.L.P. was supported by the Francois Wallace Monahan Postdoctoral Fellowship at The Rockefeller University and the European Molecular Biology Organization Long-Term Fellowship (ALTF 380–2018).

Given space constraints and the extensive literature on SARS-CoV-2, this concise review focuses on only a subset of ISGs known to influence the virus. We apologize to the many colleagues whose work was not cited and discussed.

Footnotes

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Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Declaration of Generative AI and AI- assisted technologies in the writing process

During the preparation of this work the authors utilized Open AI Chat GPT 4.0 to refine the language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Selected references

Outstanding interest

[20] An in-depth review of the diverse roles of ISGs in restricting viral entry.

[23] A CRISPR KO screen for ISGs in A549-ACE2 cells identifies DAXX and IFI6 as antiviral agents against SARS-CoV-2.

[25] Unbiased pooled CRISPR KO genetic screens in A549-ACE2 and Huh-7.5 cells, with or without type II IFN, identified PLSCR1 as a critical ISG that restricts SARS-CoV-2 entry. PLSCR1 is found within vesicles containing SARS-CoV-2, where it blocks the spike-mediated virus-cell membrane fusion process.

[26] An unbiased arrayed CRISPR KO genetic screen in Huh-7.5 cells infected with SARS-CoV-2, with or without Type I IFN pre-treatment, revealed both IFN-dependent and independent antiviral mechanisms. PLSCR1 was identified as a key ISG that blocks SARS-CoV-2 entry. Notably, PLSCR1 is not necessary for type I IFN signaling, and its intrinsic levels are sufficient for restricting SARS-CoV-2 infection without IFN.

[35] SARS-CoV-2 infection triggers the activation of the OAS-RNase L pathway in Calu-3 and A549-ACE2 lung-derived cell lines. This finding indicates that, unlike other coronaviruses, SARS-CoV-2 is unable to antagonize these host defense mechanisms.

[39] A common OAS1 haplotype is associated with increased COVID-19 severity and reduced SARS-CoV-2 clearance. This haplotype leads to decreased OAS1 expression.

[41] A genetic screen identifies 65 interferon-stimulated genes (ISGs) that influence SARS-CoV-2 infection when overexpressed in 293T-ACE2-TMPRSS2 cells. Importantly, BST2 hinders SARS-CoV-2 release and is counteracted by the SARS-CoV-2 protein Orf7a.

[89] Immune cell subsets need Ly6e expression to control murine coronavirus. Mice deficient in Ly6e are more susceptible to the Gamma (P.1) variant of SARS-CoV-2 than wildtype mice or mice lacking type I and type III interferon signaling. This highlights the importance of the intrinsic function of Ly6e in immune response.

Special interest

[1] A concise review of the induction of the IFN response by SARS-CoV-2 and its evasion strategies.

[2] A concise review of the role of IFN in restricting SARS-CoV-2 in vivo.

[22] CRISPR activation is employed in an ISG overexpression screen that identifies OAS1 as an antiviral factor in A549-ACE2 cells. Overexpression of both OAS1 p42 and p46 isoforms restricts SARS-CoV-2 infection.

[32] NCOA7 limits the endocytic entry route of SARS-CoV-2 but does not restrict the TMPRSS2-mediated entry route involving fusion with the plasma membrane.

[33] An ISG overexpression (OE) screen was carried out in interferon regulatory factor 3 (IRF3)-deficient A549 cells, A549-ACE2 cells, which have a reduced ability to produce interferon (IFN). This screen identified a subset of ISGs that restrict SARS-CoV-2, including NCOA7 and OAS1. An antiviral effect for OAS1 p46 was discovered through overexpression in A549-ACE2-TMPRSS2 cells and loss-of-function in HT1080-ACE2-TMPRSS2 cells, which mainly express p46 after IFN stimulation.

[40] This study, involving 14,134 COVID-19 cases and 1.2 million controls, notably found that an increase in circulating OAS1 levels was associated with reduced COVID-19 death or ventilation, hospitalization, and susceptibility.

[48] Endogenous IFITM expression aids SARS-CoV-2 infection in human lung cells, while artificial overexpression blocks the infection.

[81] IFITM3 promotes local lipid sorting that stabilizes hemifusion between influenza A virus and endosomal membranes. This process prevents pore formation and ultimately inhibits virus entry into target cells.

[53] IFITM3 knockout mice were infected with either the mouse-adapted MA10 or the human WA1/2020 SARS-CoV-2 strains. The WA1/2020 strain, an early clade of the SARS-CoV-2 virus, was examined in mice expressing human ACE2. Compared to wild-type mice with mild infection, IFITM3 knockout mice experience severe infection, exhibiting higher lung viral titers, increased dissemination, and heightened inflammation.

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