Identification of biomimetic nanoplatform-mediated delivery of si-ISG15 for treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is recognized as the most malicious form of breast cancer and exhibits an alarming tendency for recurrence, a heightened propensity for metastasis, and an overwhelmingly grim prognosis. Therefore, effective therapy approaches for TNBC are urgently required. In this study, the interferon-stimulated gene 15 (ISG15) expression level was analyzed by bioinformatics and verified by Western blot analysis. The effects of ISG15 on the proliferation and metastasis of TNBC cells were assessed using MTT, Colony formation, EdU, Transwell, and Flow cytometry assays. We also developed a cancer cell-biomimetic nanoparticle delivery system and evaluated its therapeutic efficacy in vivo. In this study, we reported that ISG15 was upregulated in TNBC, and its high expression level correlated with an increased risk of tumorigenesis. Through in vitro and in vivo studies, we discovered that ISG15 knockdown drastically suppressed cell proliferation, invasion, and migration and induced apoptosis in TNBC cells. Our findings revealed that ISG15 was a candidate therapeutic target in TNBC because of its key role in malignant growth and invasion. Moreover, co-immunoprecipitation showed that ISG15 exerted oncogenic functions through its interaction with ATP binding cassette subfamily E member 1 and activated the Janus kinase/signal transducers and activators of the transcription signaling pathway. Furthermore, we created a nanoparticle-based siRNA camouflaged using a cancer cell membrane vesicle delivery system (the CM@NP complex) and confirmed its therapeutic effects in vivo. Our findings confirmed that ISG15 may play a pivotal oncogenic role in the development of TNBC and that CM@siRNA-NP complexes are an effective delivery system and a novel biological strategy for treating TNBC.

Role of Viral Envelope Proteins in Determining Susceptibility of Viruses to IFITM Proteins.

Interferon-induced transmembrane proteins (IFITMs) are a family of proteins which inhibit infections of various enveloped viruses. While their general mechanism of inhibition seems to be non-specific, involving the tightening of membrane structures to prevent fusion between the viral envelope and cell membrane, numerous studies have underscored the importance of viral envelope proteins in determining the susceptibility of viruses to IFITMs. Mutations in envelope proteins may lead to viral escape from direct interaction with IFITM proteins or result in indirect resistance by modifying the viral entry pathway, allowing the virus to modulate its exposure to IFITMs. In a broader context, the nature of viral envelope proteins and their interaction with IFITMs can play a crucial role in the context of adaptive immunity, leading to viral envelope proteins that are more susceptible to antibody neutralization. The precise mechanisms underlying these observations remain unclear, and further studies in this field could contribute to a better understanding of how IFITMs control viral infections.

The population context is a driver of the heterogeneous response of epithelial cells to interferons.

Isogenic cells respond in a heterogeneous manner to interferon. Using a micropatterning approach combined with high-content imaging and spatial analyses, we characterized how the population context (position of a cell with respect to neighboring cells) of epithelial cells affects their response to interferons. We identified that cells at the edge of cellular colonies are more responsive than cells embedded within colonies. We determined that this spatial heterogeneity in interferon response resulted from the polarized basolateral interferon receptor distribution, making cells located in the center of cellular colonies less responsive to ectopic interferon stimulation. This was conserved across cell lines and primary cells originating from epithelial tissues. Importantly, cells embedded within cellular colonies were not protected from viral infection by apical interferon treatment, demonstrating that the population context-driven heterogeneous response to interferon influences the outcome of viral infection. Our data highlights that the behavior of isolated cells does not directly translate to their behavior in a population, placing the population context as one important factor influencing heterogeneity during interferon response in epithelial cells.

Melatonin inhibits atrazine-induced mitochondrial impairment in cerebellum of mice: Modulation of cGAS-STING-NLRP3 axis-dependent cell pyroptosis.

The global prevalence of Neurological disorders has increased alarmingly in response to environmental and lifestyle changes. Atrazine (ATZ) is a difficult to degrade soil and water pollutant with well-known neurotoxicity. Melatonin (MT), an antioxidant with chemoprotective properties, has a potential therapeutic effect on cerebellar damage caused by ATZ exposure. The aim of this study was to explore the effects and underlying mechanisms of MT on the cerebellar inflammatory response and pyroptosis induced by ATZ exposure. In this study, C57BL/6J mice were treated with ATZ (170 mg/kg BW/day) and MT (5 mg/kg BW/day) for 28 days. Our results revealed that MT alleviated the histopathological changes, ultrastructural damage, oxidative stress and decrease of mitochondrial membrane potential (ΔΨm) in the cerebellum induced by ATZ exposure. ATZ exposure damaged the mitochondria leading to release of mitochondrial DNA (mtDNA) to the cytoplasm, MT activated the cyclic GMP-AMP synthetase interferon gene stimulator (cGAS-STING) axis to alleviate inflammation and pyroptosis caused by ATZ exposure. In general, our study provided new evidence that the cGAS-STING-NLRP3 axis plays an important role in the treatment of ATZ-induced cerebellar injury by MT.

Interferon lambda receptor-1 isoforms differentially influence gene expression and HBV replication in stem cell-derived hepatocytes.

BACKGROUND: In the tolerogenic liver, inadequate or ineffective interferon signaling fails to clear chronic HBV infection. Lambda IFNs (IFNL) bind the interferon lambda receptor-1 (IFNLR1) which dimerizes with IL10RB to induce transcription of antiviral interferon-stimulated genes (ISG). IFNLR1 is expressed on hepatocytes, but low expression may limit the strength and antiviral efficacy of IFNL signaling. Three IFNLR1 transcriptional variants are detected in hepatocytes whose role in regulation of IFNL signaling is unclear: a full-length and signaling-capable form (isoform 1), a form that lacks a portion of the intracellular JAK1 binding domain (isoform 2), and a secreted form (isoform 3), the latter two predicted to be signaling defective. We hypothesized that altering expression of IFNLR1 isoforms would differentially impact the hepatocellular response to IFNLs and HBV replication. METHODS: Induced pluripotent stem-cell derived hepatocytes (iHeps) engineered to contain FLAG-tagged, doxycycline-inducible IFNLR1 isoform constructs were HBV-infected then treated with IFNL3 followed by assessment of gene expression, HBV replication, and cellular viability. RESULTS: Minimal overexpression of IFNLR1 isoform 1 markedly augmented ISG expression, induced de novo proinflammatory gene expression, and enhanced inhibition of HBV replication after IFNL treatment without adversely affecting cell viability. In contrast, overexpression of IFNLR1 isoform 2 or 3 partially augmented IFNL-induced ISG expression but did not support proinflammatory gene expression and minimally impacted HBV replication. CONCLUSIONS: IFNLR1 isoforms differentially influence IFNL-induced gene expression and HBV replication in hepatocytes. Regulated IFNLR1 expression in vivo could limit the capacity of this pathway to counteract HBV replication.

The Distinct Properties of Polysaccharide Nanoparticles Tune Immune Responses against mRNA Antigen via Stimulator of Interferon Genes-Mediated Autophagy and Inflammasome.

mRNA antigens require powerful nanocarriers for efficient delivery, as well as immunomodulators for controlling their excessive immunogenicity. While lipid nanoparticles (LNPs) used in mRNA vaccines exhibited systemic toxicity, there is an urgent need for developing potential nanoparticles with strong immunoenhancing effects for mRNA antigens. Although natural polysaccharides as adjuvants assisted various types of antigens in triggering potent immune responses, they have been rarely investigated in mRNA vaccines. Here, we constructed four polysaccharide nanoparticles with different molecular weights (MWs) to deliver and protect mRNA antigens, and boosted antigen cross-presentation, DC maturation, CD4+/CD8+T cell responses and humoral immune responses. Importantly, the immunoenhancing capacities of polysaccharide nanoparticles were highly dependent on their MW properties. CS NPs with high MW initiated stimulator of interferon genes (STING)-mediated autophagy and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome signaling, consequently possessing superior mRNA antigen-specific immune responses in vitro and in vivo. In contrast, CS NPs with low MWs induced NLRP3 signaling without STING or autophagy activation, which failed to induce robust immune responses. Therefore, it uncovered the MW-dependent immunoenhancing effects and mechanism of polysaccharide nanoparticles, providing a platform for designing potential nanosized polysaccharide immunomodulators for mRNA vaccines.

Mechanisms of antiviral activity of the new hDHODH inhibitor MEDS433 against respiratory syncytial virus replication.

Human respiratory syncytial virus (RSV) is an important cause of acute lower respiratory infections, for which no effective drugs are currently available. The development of new effective anti-RSV agents is therefore an urgent priority, and Host-Targeting Antivirals (HTAs) can be considered to target RSV infections. As a contribution to this antiviral avenue, we have characterized the molecular mechanisms of the anti-RSV activity of MEDS433, a new inhibitor of human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of de novo pyrimidine biosynthesis. MEDS433 was found to exert a potent antiviral activity against RSV-A and RSV-B in the one-digit nanomolar range. Analysis of the RSV replication cycle in MEDS433-treated cells, revealed that the hDHODH inhibitor suppressed the synthesis of viral genome, consistently with its ability to specifically target hDHODH enzymatic activity. Then, the capability of MEDS433 to induce the expression of antiviral proteins encoded by Interferon-Stimulated Genes (ISGs) was identified as a second mechanism of its antiviral activity against RSV. Indeed, MEDS433 stimulated secretion of IFN-ß and IFN-λ1 that, in turn, induced the expression of some ISG antiviral proteins, such as IFI6, IFITM1 and IRF7. Singly expression of these ISG proteins reduced RSV-A replication, thus likely contributing to the overall anti-RSV activity of MEDS433. Lastly, MEDS433 proved to be effective against RSV-A replication even in a primary human small airway epithelial cell model. Taken as a whole, these observations provide new insights for further development of MEDS433, as a promising candidate to develop new strategies for treatment of RSV infections.

Effect of Interferon Gamma on Ebola Virus Infection of Primary Kupffer Cells and a Kupffer Cell Line.

Ebola virus disease (EVD) represents a global health threat. The etiological agents of EVD are six species of Orthoebolaviruses, with Orthoebolavirus zairense (EBOV) having the greatest public health and medical significance. EVD pathogenesis occurs as a result of broad cellular tropism of the virus, robust viral replication and a potent and dysregulated production of cytokines. In vivo, tissue macrophages are some of the earliest cells infected and contribute significantly to virus load and cytokine production. While EBOV is known to infect macrophages and to generate high titer virus in the liver, EBOV infection of liver macrophages, Kupffer cells, has not previously been examined in tissue culture or experimentally manipulated in vivo. Here, we employed primary murine Kupffer cells (KC) and an immortalized murine Kupffer cell line (ImKC) to assess EBOV-eGFP replication in liver macrophages. KCs and ImKCs were highly permissive for EBOV infection and IFN-γ polarization of these cells suppressed their permissiveness to infection. The kinetics of IFN-γ-elicited antiviral responses were examined using a biologically contained model of EBOV infection termed EBOV ΔVP30. The antiviral activity of IFN-γ was transient, but a modest ~3-fold reduction of infection persisted for as long as 6 days post-treatment. To assess the interferon-stimulated gene products (ISGs) responsible for protection, the efficacy of secreted ISGs induced by IFN-γ was evaluated and secreted ISGs failed to block EBOV ΔVP30. Our studies define new cellular tools for the study of EBOV infection that can potentially aid the development of new antiviral therapies. Furthermore, our data underscore the importance of macrophages in EVD pathogenesis and those IFN-γ-elicited ISGs that help to control EBOV infection.

Nascent transcription upon interferon-α2 stimulation on human and rhesus macaque lymphoblastoid cell lines.

OBJECTIVES: The interferon-triggered innate immune response has been observed to be under strong diversifying selection to counteract the many pathogens hosts have to defend against. In particular, rewiring of gene transcription regulation allows organisms to rapidly acquire new phenotypes by removing and adding genes into the innate immune gene network. Dissecting the molecular processes by which this rewiring takes place, either by changing the DNA regulatory elements or by changing the activity of the regulators across species, is key to better understand this evolutionary process. DATA DESCRIPTION: To better comprehend the evolutionary dynamics that have occurred in the initial transcriptional response to interferon in primates, we present Precision Run-On (PRO-seq) datasets made after 1 h of interferon-α2 stimulation on human and rhesus macaque lymphoblastoid cell lines. Further, we tested the difference between using either species' cognate interferon versus using the other orthologous interferon to account for any potential impacts in the interaction of the orthologous interferons with their cellular membrane receptors. This data provides insights into the regulatory mechanisms that drive species-specific responses to environmental perturbations, such as the one driven by the interactions of pathogens and their hosts.

The STING-IRF3 Signaling Pathway, Mediated by Endoplasmic Reticulum Stress, Contributes to Impaired Myocardial Autophagic Flux After Ischemia/Reperfusion.

ABSTRACT: This study aimed to determine whether endoplasmic reticulum (ER) stress is involved in impaired autophagy after myocardial ischemia/reperfusion (M-I/R) and elucidate the underlying mechanisms. The expression levels of stimulator of interferon gene (STING) and interferon regulatory transcription factor 3 (IRF3) phosphorylation increased in M-I/R heart tissues and hypoxia-treated/reoxygenation-treated H9c2 cells. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) significantly suppressed the stimulation of STING-IRF3 transcription and alleviated cardiac dysfunction caused by M-I/R injury. In addition, 4-PBA reversed ischemia-induced/reperfusion-induced autophagic flux dysfunction, as demonstrated by a decrease in p 62 and LC3 levels. Similarly, the protective effect of STING deficiency on myocardial cell damage was achieved by the recovery of autophagic flux. Conversely, the protective effect of 4-PBA against hypoxia/reoxygenation injury in cardiomyocytes was offset by STING overexpression, wherein the activated STING-IRF3 pathway promoted the expression of Rubicon (a negatively-regulated autophagic molecule) by binding to the Rubicon promoter. Rubicon ablation effectively counteracts the adverse effects of STING overexpression in cardiomyocytes. The data showed that STING-IRF3 signaling of ER stress receptors is particularly important in the progression of physiological M-I/R caused by the inhibition of autophagic flow in vivo and in vitro.

Discovery of novel amidobenzimidazole derivatives as orally available small molecule modulators of stimulator of interferon genes for cancer immunotherapy.

Stimulator of interferon genes (STING) agonists show promise as immunomodulatory agents for cancer therapy. In this study, we report the discovery of a novel orally available STING agonist, SAP-04, that exhibits potent immunomodulatory effects for cancer therapy. By optimizing the amidobenzimidazole core with various pyridine-based heterocyclic substituents, we identified a monomeric variant that displayed more efficient STING agonistic activity than the corresponding dimer. SAP-04 efficiently induced cytokine secretion related to innate immunity by directly binding of the compound to the STING protein, followed by sequential signal transduction for the STING signaling pathway and type I interferon (IFN) responses. Further pharmacological validation in vitro and in vivo demonstrated the potential utility of SAP-04 as an immunomodulatory agent for cancer therapy in vivo. The in vivo anticancer effect was observed in a 4T1 breast tumor syngeneic mouse model through oral administration of the compound. Our findings suggest a possible strategy for developing synthetically accessible monomeric variants as orally available STING agonists.

25-hydroxycholesterol: an integrator of antiviral ability and signaling.

Cholesterol, as an important component in mammalian cells, is efficient for viral entry, replication, and assembly. Oxysterols especially hydroxylated cholesterols are recognized as novel regulators of the innate immune response. The antiviral ability of 25HC (25-Hydroxycholesterol) is uncovered due to its role as a metabolic product of the interferon-stimulated gene CH25H (cholesterol-25-hydroxylase). With the advancement of research, the biological functions of 25HC and its structural functions have been interpreted gradually. Furthermore, the underlying mechanisms of antiviral effect of 25HC are not only limited to interferon regulation. Taken up by the special biosynthetic ways and structure, 25HC contributes to modulate not only the cholesterol metabolism but also autophagy and inflammation by regulating signaling pathways. The outcome of modulation by 25HC seems to be largely dependent on the cell types, viruses and context of cell microenvironments. In this paper, we review the recent proceedings on the regulatory effect of 25HC on interferon-independent signaling pathways related to its antiviral capacity and its putative underlying mechanisms.

Janus kinase-inhibition modulates hepatitis E virus infection.

Hepatitis E virus (HEV) usually causes a self-limiting disease, but especially immunocompromised individuals are at risk to develop a chronic and severe course of infection. Janus kinase (JAK) inhibitors (JAKi) are a novel drug class for the treatment of autoimmune inflammatory rheumatic disease (AIRD). As JAKs play a key role in innate immunity, viral infections and reactivations are frequently reported during JAKi treatment in AIRD patients. The aim of this study was to characterize the influence of JAKis on HEV replication. To this end, we evaluated liver enzymes of an AIRD patient under JAKi therapy with hepatitis E. Further, experiments with HEV (Kernow-C1 p6) were performed by infection of primary human hepatocytes (PHHs) followed by immunofluorescence staining of viral markers and transcriptomic analysis. Infection experiments in PHHs displayed an up to 50-fold increase of progeny virus production during JAKi treatment and transcriptomic analysis revealed induction of antiviral programs during infection. Upregulation of interferon-stimulated genes (ISG) was perturbed in the presence of JAKis, concomitant with elevated HEV RNA levels. The obtained results suggest that therapeutic JAK inhibition increases HEV replication by modulating the HEV-triggered immune response. Therefore, JAKi treatment and the occurrence of elevated liver enzymes requires a monitoring of potential HEV infections.

The role of Type I interferons in the pathogenesis of foot-and-mouth disease virus in cattle: A mathematical modelling analysis.

Type I interferons (IFN) are the first line of immune response against infection. In this study, we explore the interaction between Type I IFN and foot-and-mouth disease virus (FMDV), focusing on the effect of this interaction on epithelial cell death. While several mathematical models have explored the interaction between interferon and viruses at a systemic level, with most of the work undertaken on influenza and hepatitis C, these cannot investigate why a virus such as FMDV causes extensive cell death in some epithelial tissues leading to the development of lesions, while other infected epithelial tissues exhibit negligible cell death. Our study shows how a model that includes epithelial tissue structure can explain the development of lesions in some tissues and their absence in others. Furthermore, we show how the site of viral entry in an epithelial tissue, the viral replication rate, IFN production, suppression of viral replication by IFN and IFN release by live cells, all have a major impact on results.

Deficiency of SCAP inhibits HBV pathogenesis via activation of the interferon signaling pathway.

Hepatitis B virus (HBV) infects the liver and is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Approaches for an effective cure are thwarted by limited knowledge of virus-host interactions. Herein, we identified SCAP as a novel host factor that regulates HBV gene expression. SCAP, sterol regulatory element-binding protein (SREBP) cleavage-activating protein, is an integral membrane protein located in the endoplasmic reticulum. The protein plays a central role in controlling lipid synthesis and uptake by cells. We found that gene silencing of SCAP significantly inhibited HBV replication; furthermore, knockdown of SREBP2 but not SREBP1, the downstream effectors of SCAP, reduced HBs antigen production from HBV infected primary hepatocytes. We also demonstrated that knockdown of SCAP resulted in activation of interferons (IFNs) and IFN stimulated genes (ISGs). Conversely, ectopic expression of SREBP2 in SCAP-deficient cells restored expression of IFNs and ISGs. Importantly, expression of SREBP2 restored HBV production in SCAP knockdown cells, suggesting that SCAP participates in HBV replication through an effect on IFN production via its downstream effector SREBP2. This observation was further confirmed by blocking IFN signaling by an anti-IFN antibody, which restored HBV infection in SCAP-deficient cells. This led to the conclusion that SCAP regulates the IFN pathway through SREBP, thereby affecting the HBV lifecycle. This is the first study to reveal the involvement of SCAP in regulation of HBV infection. These results may facilitate development of new antiviral strategies against HBV.

Hypoxia-altered cholesterol homeostasis enhances the expression of interferon-stimulated genes upon SARS-CoV-2 infections in monocytes.

Hypoxia contributes to numerous pathophysiological conditions including inflammation-associated diseases. We characterized the impact of hypoxia on the immunometabolic cross-talk between cholesterol and interferon (IFN) responses. Specifically, hypoxia reduced cholesterol biosynthesis flux and provoked a compensatory activation of sterol regulatory element-binding protein 2 (SREBP2) in monocytes. Concomitantly, a broad range of interferon-stimulated genes (ISGs) increased under hypoxia in the absence of an inflammatory stimulus. While changes in cholesterol biosynthesis intermediates and SREBP2 activity did not contribute to hypoxic ISG induction, intracellular cholesterol distribution appeared critical to enhance hypoxic expression of chemokine ISGs. Importantly, hypoxia further boosted chemokine ISG expression in monocytes upon infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Mechanistically, hypoxia sensitized toll-like receptor 4 (TLR4) signaling to activation by SARS-CoV-2 spike protein, which emerged as a major signaling hub to enhance chemokine ISG induction following SARS-CoV-2 infection of hypoxic monocytes. These data depict a hypoxia-regulated immunometabolic mechanism with implications for the development of systemic inflammatory responses in severe cases of coronavirus disease-2019 (COVID-19).

The value of Interferon ß in multiple sclerosis and novel opportunities for its anti-viral activity: a narrative literature review.

Interferon-beta (IFN-ß) for Multiple Sclerosis (MS) is turning 30. The COVID-19 pandemic rejuvenated the interest in interferon biology in health and disease, opening translational opportunities beyond neuroinflammation. The antiviral properties of this molecule are in accord with the hypothesis of a viral etiology of MS, for which a credible culprit has been identified in the Epstein-Barr Virus. Likely, IFNs are crucial in the acute phase of SARS-CoV-2 infection, as demonstrated by inherited and acquired impairments of the interferon response that predispose to a severe COVID-19 course. Accordingly, IFN-ß exerted protection against SARS-CoV-2 in people with MS (pwMS). In this viewpoint, we summarize the evidence on IFN-ß mechanisms of action in MS with a focus on its antiviral properties, especially against EBV. We synopsize the role of IFNs in COVID-19 and the opportunities and challenges of IFN-ß usage for this condition. Finally, we leverage the lessons learned in the pandemic to suggest a role of IFN-ß in long-COVID-19 and in special MS subpopulations.

Restriction of SARS-CoV-2 replication by receptor transporter protein 4 (RTP4).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is subject to restriction by several interferon-inducible host proteins. To identify novel factors that limit replication of the virus, we tested a panel of genes that we found were induced by interferon treatment of primary human monocytes by RNA sequencing. Further analysis showed that one of the several candidates genes tested, receptor transporter protein 4 (RTP4), that had previously been shown to restrict flavivirus replication, prevented the replication of the human coronavirus HCoV-OC43. Human RTP4 blocked the replication of SARS-CoV-2 in susceptible ACE2.CHME3 cells and was active against SARS-CoV-2 Omicron variants. The protein prevented the synthesis of viral RNA, resulting in the absence of detectable viral protein synthesis. RTP4 bound the viral genomic RNA and the binding was dependent on the conserved zinc fingers in the amino-terminal domain. Expression of the protein was strongly induced in SARS-CoV-2-infected mice although the mouse homolog was inactive against the virus, suggesting that the protein is active against another virus that remains to be identified. IMPORTANCE The rapid spread of a pathogen of human coronavirus (HCoV) family member, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), around the world has led to a coronavirus disease 2019 (COVID-19) pandemic. The COVID-19 pandemic spread highlights the need for rapid identification of new broad-spectrum anti-coronavirus drugs and screening of antiviral host factors capable of inhibiting coronavirus infection. In the present work, we identify and characterize receptor transporter protein 4 (RTP4) as a host restriction factor that restricts coronavirus infection. We examined the antiviral role of hRTP4 toward the coronavirus family members including HCoV-OC43, SARS-CoV-2, Omicron BA.1, and BA.2. Molecular and biochemical analysis showed that hRTP4 binds to the viral RNA and targets the replication phase of viral infection and is associated with reduction of nucleocapsid protein. Significant higher levels of ISGs were observed in SARS-CoV-2 mouse model, suggesting the role of RTP4 in innate immune regulation in coronavirus infection. The identification of RTP4 reveals a potential target for therapy against coronavirus infection.

Interfering with Interferons: A Critical Mechanism for Critical COVID-19 Pneumonia.

Infection with SARS-CoV-2 results in clinical outcomes ranging from silent or benign infection in most individuals to critical pneumonia and death in a few. Genetic studies in patients have established that critical cases can result from inborn errors of TLR3- or TLR7-dependent type I interferon immunity, or from preexisting autoantibodies neutralizing primarily IFN-α and/or IFN-ω. These findings are consistent with virological studies showing that multiple SARS-CoV-2 proteins interfere with pathways of induction of, or response to, type I interferons. They are also congruent with cellular studies and mouse models that found that type I interferons can limit SARS-CoV-2 replication in vitro and in vivo, while their absence or diminution unleashes viral growth. Collectively, these findings point to insufficient type I interferon during the first days of infection as a general mechanism underlying critical COVID-19 pneumonia, with implications for treatment and directions for future research.

Targeting TAF1 with BAY-299 induces antitumor immunity in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype with poor prognoses and limited therapeutic options. The TATA-box binding protein associated factor 1 (TAF1) is an essential protein involved in the transcriptional regulation of cancer development and progress. However, the therapeutic potential and underlying mechanism of targeting TAF1 in TNBC remain unknown. Here, using chemical probe BAY-299, we identify that TAF1 inhibition leads to the induction of endogenous retrovirus (ERVs) expression and double-stranded RNA (dsRNA) formation, resulting in the activation of interferon responses and cell growth suppression in a subset of TNBC, resembling anti-viral mimicry effect. This correlation between TAF1 and interferon signature was validated in three independent breast cancer patient datasets. Furthermore, we observe heterogeneous responses to TAF1 inhibition across a set of TNBC cell lines. By integrating transcriptome and proteome data, we demonstrate that high levels of proliferating cell nuclear antigen (PCNA) protein serve as a predictive biomarker associated with suppressive tumor immune responses in various cancers, which may limit the efficiency of TAF1 inhibition.