A new mechanism of interferon’s antiviral action: Induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene, TDRD7

Subramanian, G. Mani; Kuzmanovic, Teodora; Zhang, Ying; Peter, Cara; Veleeparambil, Manoj; Chakravarti, Ritu; Sen, Ganes C.; Chattopadhyay, Saurabh

doi:10.1371/journal.ppat.1006877

Cited by 59 publications

(71 citation statements)

References 75 publications

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“…Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue exclusion, and brightfield microscopy. To measure cell viability, the cells were seeded in a 96-well plate, and transfected (RLR) or treated (TLR3) with polyI:C in the absence or the presence of doxorubicin or vehicle (DMSO), as indicated, for 24 h. The MTT assay was performed using previously described procedures [26]. The absorbance of the treated cells was considered as 100, and the other values were normalized to this.…”

Section: Cell Viability Assaysmentioning

confidence: 99%

High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication

Glanz

Chawla

Fabry

et al. 2020

Viruses

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Interferon (IFN) regulatory factor 3 (IRF3) is the key transcription factor for the induction of IFN and antiviral genes. The absence of antiviral genes in IRF3 deficiency leads to susceptibility to a wide range of viral infections. Previously, we uncovered a function for nontranscriptional IRF3 (nt-IRF3), RLR (RIG-I-like receptor)-induced IRF3-mediated pathway of apoptosis (RIPA), which triggers apoptotic killing of virus-infected cells. Using knock-in mice expressing a transcriptionally inactive, but RIPA-active, IRF3 mutant, we demonstrated the relative contribution of RIPA to host antiviral defense. Given that RIPA is a cellular antiviral pathway, we hypothesized that small molecules that promote RIPA in virus-infected cells would act as antiviral agents. To test this, we conducted a high throughput screen of a library of FDA-approved drugs to identify novel RIPA activators. Our screen identified doxorubicin as a potent RIPA-activating agent. In support of our hypothesis, doxorubicin inhibited the replication of vesicular stomatitis virus, a model rhabdovirus, and its antiviral activity depended on its ability to activate IRF3 in RIPA. Surprisingly, doxorubicin inhibited the transcriptional activity of IRF3. The antiviral activity of doxorubicin was expanded to flavivirus and herpesvirus that also activate IRF3. Mechanistically, doxorubicin promoted RIPA by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Finally, we validated these results using another RIPA-activating compound, pyrvinium pamoate, which showed a similar antiviral effect without affecting the transcriptional activity of IRF3. Therefore, we demonstrate that the RIPA branch of IRF3 can be targeted therapeutically to prevent virus infection.

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Section: Cell Viability Assaysmentioning

confidence: 99%

High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication

Glanz

Chawla

Fabry

et al. 2020

Viruses

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“…Autophagy pathways can be specifically targeted, according to the type of virus infection. Inhibitors of autophagy may inhibit the growth of RNA viruses that rely on the associated membranes for replication, such as Picornaviruses and Dengue .…”

Section: Finding New Uses For Approved Drugsmentioning

confidence: 99%

Repurposing approved drugs on the pathway to novel therapies

Schein

2019

Medicinal Research Reviews

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The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

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“…This suggests that there is a genetic element to susceptibility to symptomatic infection and since ISGs are vital in early viral control, they are a likely candidate. A number of ISG have been demonstrated to inhibit RSV including IFITM proteins (4, 5) TDRD7 (6), and 2′-5′ oligoadenylate synthetase (7).…”

Section: Introductionmentioning

confidence: 99%

Interferon-induced Protein-44 and Interferon-induced Protein 44-like restrict replication of Respiratory Syncytial Virus

Busse

Habgood-Coote

Clare

et al. 2020

Preprint

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24Cellular intrinsic immunity, mediated by the expression of an array of interferon-25 stimulated antiviral genes, is a vital part of host defence. We have previously used a 26 bioinformatic screen to identify two interferon stimulated genes (ISG) with poorly 27 characterised function, Interferon-induced protein 44 (IFI44) and interferon-induced 28 protein 44-like (IFI44L), as potentially being important in Respiratory Syncytial Virus 29 (RSV) infection. Using overexpression systems, CRISPR-Cas9-mediated knockout, 30 and a knockout mouse model we investigated the antiviral capability of these genes 31 in the control of RSV replication. Over-expression of IFI44 or IFI44L was sufficient to 32 restrict RSV infection at an early time post infection. Knocking out these genes in 33 mammalian airway epithelial cells increased levels of infection. Both genes express 34 antiproliferative factors that have no effect on RSV attachment but reduce RSV 35 replication in a minigenome assay. The loss of Ifi44 was associated with a more 36 severe infection phenotype in vivo. These studies demonstrate a function for IFI44 37 and IFI44L in controlling RSV infection. 38 Importance 39RSV infects all children under two years of age, but only a subset of children get 40 severe disease. We hypothesize that susceptibility to severe RSV necessitating 41 hospitalization in children without pre-defined risk factors is in part mediated at the 42 anti-viral gene level. But there is a large array of anti-viral genes, particularly in the 43 ISG family about which the mechanism is poorly understood. Having observed 44 significantly lower levels of IFI44 and IFI44L gene expression in hospitalized children 45 with a confirmed diagnosis of RSV, we dissected the function of these two genes. 46 Through a range of over-expression and knockout studies we show that the genes 47 are anti-viral and anti-proliferative. This study is important because IFI44 and IFI44L 48 are upregulated after a wide range of viral infections and IFI44L can serve as a 49 diagnostic bio-marker of viral infection.50 94 triphosphate (GTP)-binding region present in either protein. We demonstrate for the 95 first time that the loss of IFI44 expression in a mouse model of infection is associated 96 with more severe RSV disease.97 5 Methods 98 Clinical cohort. IFI44 and IFI44L expression was analysed in a published clinical 99 cohort of febrile infants with either moderate or severe RSV infection [13]. The 100 microarray gene expression dataset (GSE72810) was retrieved from the National 101 Institutes of Health Gene Expression Omnibus database (22) using the GEOquery 102 package (23) in R (24). Normalisation was performed using robust spline 103 normalisation (RSN) from the lumi package (25) followed by a log transformation. 104 Patients with suspected or confirmed bacterial infection were removed (n = 4). 105 Cohort demographics are described in the associated figures. Prior to differential 106 expression probes were removed if the expression was not above 6 in at least 4 107 s...

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A new mechanism of interferon’s antiviral action: Induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene, TDRD7

Cited by 59 publications

References 75 publications

High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication

High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication

Repurposing approved drugs on the pathway to novel therapies

Interferon-induced Protein-44 and Interferon-induced Protein 44-like restrict replication of Respiratory Syncytial Virus

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