NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner

Waqas, Fakhar H.; Shehata, Mahmoud; Elgaher, Walid A. M.; Lacour, Antoine; Kurmasheva, Naziia; Begnini, Fabio; Kiib, Anders; Dahlmann, Julia; Chen, Chutao; Pavlou, Andreas; Poulsen, Thomas B.; Merkert, Sylvia; Olmer, Ruth; Olagnier, David; Hirsch, Anna K. H.; Pleschka, Stephan; Peßler, Frank

doi:10.1371/journal.ppat.1011506

Cited by 17 publications

(7 citation statements)

References 47 publications

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“…Unexpectedly, we also showed that 4-OI induced a cellular antiviral program that potently inhibited a broad range of viruses including SARS-CoV-2, Herpes Simplex virus 1 and 2 (HSV-1/2), Vaccinia Virus, and Zika Virus, and that without promoting an inflammatory state 34 . This antiviral action was also observed by two other groups, reporting that 4-OI reduced influenza A virus replication by directly targeting the nuclear export protein CRM1 35 , 36 .…”

Section: Introductionsupporting

confidence: 76%

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

Kurmasheva,

Said,

Wong

et al. 2024

Nat Commun

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The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

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Section: Introductionsupporting

confidence: 76%

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

Kurmasheva,

Said,

Wong

et al. 2024

Nat Commun

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“…It is unlikely that activation of Nrf2 is the sole mechanism for the observed antiviral effect of itaconic acid, as the potent Nrf2 activator dimethyl itaconate (DI) ( 28 ) failed to restrict viral replication of IAV in a similar magnitude as 4-OI ( 4 ). In fact, a recent study suggested the antiviral properties of 4-OI to be Nrf2 independent but to interfere with IAV RNPs instead via interaction with CRM1 ( 29 ). Indeed, other antiviral mechanisms have been proposed for the activity of itaconate derivatives against influenza viruses such as targeting of the nuclear export of IAV vRNPs ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1

Ribó-Molina,

Weiss,

Susma

et al. 2023

J Virol

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In recent years, especially since the outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic, the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) has gained traction as a potential antiviral agent. Here, we demonstrate that 4-OI inhibits replication of multiple influenza A viruses (IAV) by restricting nuclear export of viral ribonucleoproteins, a key step in the IAV replication cycle. This nuclear retention is achieved by deactivation and subsequent degradation of chromosomal maintenance 1 protein (CRM1), also known as exportin 1 (XPO1), a host cell protein exploited by IAV during replication. 4-OI-mediated deactivation of CRM1 resulted in the accumulation of the IAV nucleoprotein, the Rev protein of feline immunodeficiency virus, as well as the natural CRM1 cargos p53 and p65, in the nucleus of treated cells. Further mechanism of action studies revealed that, similar to known CRM1 inhibitors, 4-OI modifies a key cysteine in the cargo binding pocket of CRM1 at position 528 through an alkylation reaction called 2,3-dicarboxypropylation. Subsequent studies in a cell line in which the cysteine at position 528 in CRM1 protein was substituted by a serine confirmed that modification of this residue was indeed the cause for the observed inhibitory effect induced by 4-OI on CRM1 function. Overall, this study demonstrated a mechanism through which 4-OI directly interferes with the replication cycle of CRM1-dependent viruses, which contributes to the understanding of the antiviral and anti-inflammatory properties of this multifaceted immuno-metabolite. IMPORTANCE Itaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral effects of exogenous 4-octyl itaconate (4-OI), a derivative of itaconate, against the influenza A virus replication is demonstrated. The data indicate that 4-OI targets the cysteine at position 528 of the CRM1 protein, resulting in inhibition of the nuclear export of viral ribonucleoprotein complexes in a similar manner as previously described for other selective inhibitors of nuclear export. These results postulate a mechanism not observed before for this immuno-metabolite derivative. This knowledge is helpful for the development of derivatives of 4-OI as potential antiviral and anti-inflammatory therapeutics.

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“…The contribution of Nrf2 pathway to antiviral effects of flavonoids and various herbal phenolic compounds remains to be elucidated in detail. Recent findings support the role of various Nrf2 activators in inhibiting influenza virus replication [39]. Catechin flavonoids have been shown to inhibit TGEV-induced ROS and cytopathic effect [40].…”

Section: Discussionmentioning

confidence: 66%

The Influence of Flavonoid Compositions on Nrf2 Transcription Factor Expression in Case of Infections Triggered by Influenza A Virus and Transmissible Gastroenteritis Coronavirus

Arkhypova,

Deriabin,

Trokhymchuk

et al. 2023

Innov Biosyst Bioeng

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Background. Viral infections trigger transcription factors, including Nrf2, which regulate the expression of genes related to cytokines, chemokines, and more. Nuclear factor erythroid 2-related factor 2 (Nrf2) participates in complex regulatory networks controlling the expression of cytoprotective genes and immune responses. Recently, new roles have been attributed to Nrf2, including the regulation of antiviral responses. Objective. The aim of the study was to analyze Nrf2 activation in influenza virus infection in vivo and in transmissible gastroenteritis coronavirus (TGEV) infection in vitro, as well as the effects of the flavonoid compositions Proteflazidum® and Protoil on the Nrf2 expression in these two experimental models of viral infection. Methods. Outbred white mice were infected with influenza A virus (A/FM/1/47/H1N1 strain). Jurkat cells were infected with TGEV, previously adapted to these cells. Flavonoid compositions Proteflazidum® and Protoil (Ecopharm, Ukraine), containing the mixture of tricin, luteolin, apigenin, quercetin, and rhamnosin, were used in corresponding dilutions. Real-Time PCR was employed to analyze Nrf2 RNA expression in the lungs of mice and in both uninfected and virus-infected cells. Additionally, ELISA was used to assess the expression of Nrf2 peptide. Results. The Nrf2 expression in the lungs of influenza virus-infected mice showed a tendency to increase within a 100-fold range. In virus-infected mice treated with Proteflazidum® or Protoil, the level of Nrf2 expression in the lungs decreased about 10-fold compared to infected untreated mice. TGEV infection resulted in 100-fold increase in Nrf2 expression in Jurkat cells. Both Proteflazidum® and Protoil decreased Nrf2 expression in TGEV-infected cells, while their effects on Nrf2 expression in the intact cells on Day 1 were not detected. Conclusions. Flavonoid compositions have only a slight effect on Nrf2 expression in intact cells. However, in case of virus infection, both in vivo and in vitro, they counteract the extensive up-regulation of Nrf2 expression due to viral infection.

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NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner

Cited by 17 publications

References 47 publications

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1

The Influence of Flavonoid Compositions on Nrf2 Transcription Factor Expression in Case of Infections Triggered by Influenza A Virus and Transmissible Gastroenteritis Coronavirus

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