Convergent Transcription of Interferon-stimulated Genes by TNF-α and IFN-α Augments Antiviral Activity against HCV and HEV

Wang, Wenshi; Xu, Lei; Brandsma, J; Wang, Yijin; Hakim, Mohamad S.; Zhou, Xinying; Yin, Yuebang; Fuhler, Gwenny M.; Laan, Luc J. W. van der; Woude, C. Janneke van der; Sprengers, Dave; Metselaar, Herold J.; Smits, Ron; Poot, Raymond A.; Peppelenbosch, Maikel P.

doi:10.1038/srep25482

Cited by 54 publications

(64 citation statements)

References 39 publications

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“…Nuclear factor-kappa B (NF-B) signaling participates in modulating the activation of various proinflammatory cytokine genes and ISGs (20), contributing to a vital role in combating pathogen invasion. By using Huh7 and Caco-2 cell-based NF-B luciferase reporter cells, we further excluded the activation of the NF-B pathway by TZD (see the supplemental material).…”

Section: Irf-1 Inhibited Hunv Replication and Contributed To The Tzd-mentioning

confidence: 99%

Nitazoxanide Inhibits Human Norovirus Replication and Synergizes with Ribavirin by Activation of Cellular Antiviral Response

Wen

et al. 2018

Antimicrob Agents Chemother

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Norovirus is the main cause of viral gastroenteritis worldwide. Although norovirus gastroenteritis is self-limiting in immunocompetent individuals, chronic infections with debilitating and life-threatening complications occur in immunocompromised patients. Nitazoxanide (NTZ) has been used empirically in the clinic and has demonstrated effectiveness against norovirus gastroenteritis. In this study, we aimed at uncovering the antiviral potential and mechanisms of action of NTZ and its active metabolite, tizoxanide (TIZ), using a human norovirus (HuNV) replicon. NTZ and TIZ, collectively referred to as thiazolides (TZD), potently inhibited replication of HuNV and a norovirus surrogate, feline calicivirus. Mechanistic studies revealed that TZD activated cellular antiviral response and stimulated the expression of a subset of interferon-stimulated genes (ISGs), particularly interferon regulatory factor 1 (IRF-1), not only in a Huh7 cell-based HuNV replicon, but also in naive Huh7 and Caco-2 cells and novel human intestinal organoids. Overexpression of exogenous IRF-1 inhibited HuNV replication, whereas knockdown of IRF-1 largely attenuated the antiviral activity of TZD, suggesting that IRF-1 mediated TZD inhibition of HuNV. By using a Janus kinase (JAK) inhibitor, CP-690550, and a STAT1 knockout approach, we found that TZD induced antiviral response independently of the classical JAK-signal transducers and activators of transcription (JAK-STAT) pathway. Furthermore, TZD and ribavirin synergized to inhibit HuNV replication and completely depleted the replicons from host cells after long-term treatment. In summary, our results demonstrated that TZD combated HuNV replication through activation of cellular antiviral response, in particular by inducing a prominent antiviral effector, IRF-1. NTZ monotherapy or combination with ribavirin represent promising options for treating norovirus gastroenteritis, especially in immunocompromised patients.

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Section: Irf-1 Inhibited Hunv Replication and Contributed To The Tzd-mentioning

confidence: 99%

Nitazoxanide Inhibits Human Norovirus Replication and Synergizes with Ribavirin by Activation of Cellular Antiviral Response

Wen

et al. 2018

Antimicrob Agents Chemother

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“…Studies have shown that type I IFN treatment induces degradation of IB␣, increasing NF-B p65/p50-mediated transcription of antiviral ISGs, such as Mx1 and Nmi (8). Moreover, different groups have provided evidence that type I IFNs and TNF-␣ work together to protect the host from lethal virus infection by enhancing transcription of antiviral ISGs through activation of both JAK/STAT and NF-B signaling pathways (19,30). Interestingly, our data suggest that Slfn2 plays a key role in the regulation/balance of type I IFN-mediated activation of STAT1 and NF-B.…”

Section: Discussionmentioning

confidence: 99%

“…4). Studies have shown that IFN-␤ induces activation of NF-B through both canonical and noncanonical pathways and that the promoter regions of ISGs have binding sites for NF-B (9,19). Accordingly, we next investigated the role of Slfn2 in type I IFN-induced activation of the NF-B signaling pathway.…”

Section: Absence Of Slfn2 Expression Enhances Ifn-␤-inducible Transcrmentioning

confidence: 99%

Slfn2 Regulates Type I Interferon Responses by Modulating the NF-κB Pathway

Fischietti

Arslan

Sassano

et al. 2018

Molecular and Cellular Biology

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Although members of the Slfn family have been implicated in the regulation of type I interferon (IFN) responses, the mechanisms by which they mediate their effects remain unknown. In the present study we provide evidence that targeted disruption of gene leads to increased transcription of IFN-stimulated genes (ISGs) and enhanced type I IFN-mediated antiviral responses. We demonstrate that Slfn2 interacts with protein phosphatase 6 regulatory subunit 1 (PPP6R1), leading to reduced type I IFN-induced activation of nuclear factor kappa B (NFĸB) signaling, resulting in reduced expression of ISGs. Altogether these data suggest a novel mechanism by which Slfn2 controls ISG expression and provide evidence for a critical role for Slfn2 in the regulation of IFN-mediated biological responses.

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“…TNF-α plays several therapeutic roles within the body, including immunostimulation, resistance to tumors, and sleep regulation2650. TNF-α is also an important mediator of resistance against infectious diseases225152535455. For example, in experimental leishmaniasis, insufficient TNF-α is associated with progressive disease and death53.…”

Section: Discussionmentioning

confidence: 99%

Identification of a TNF-α inducer MIC3 originating from the microneme of non-cystogenic, virulent Toxoplasma gondii

Qiu

Wang

Zhang

et al. 2016

Sci Rep

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Toxoplasma gondii is an opportunistic parasite with avirulent cystogenic and highly virulent non-cystogenic isolates. Although non-cystogenic strains are considered the most virulent, there are also marked genetic and virulence differences among these strains. Excretory-secretory antigens (ESAs) of T. gondii are critical for the invasion process and the immune response of the host. To better understand the differences in virulence between non-cystogenic T. gondii isolates, we studied ESAs of the RH strain (Type I), and the very prevalent in China, but less virulent TgCtwh3 strain (Chinese 1). ESAs of RH and TgCtwh3 triggered different levels of TNF-α production and macrophage M1 polarization. Using iTRAQ analysis, 27 differentially expressed proteins originating from secretory organelles and surface were quantified. Of these proteins, 11 microneme-associated proteins (MICs), 6 rhoptry proteins, 2 dense granule proteins and 5 surface proteins were more abundant in RH than in TgCtwh3. The protein-protein correlation network was employed to identify the important functional node protein MIC3, which was upregulated 5-fold in RH compared with TgCtwh3. MIC3 was experimentally confirmed to evoke a TNF-α secretory response, and it also induced macrophage M1 polarization. This result suggests that MIC3 is a potentially useful immunomodulator that induces TNF-α secretion and macrophage M1 polarization.

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Convergent Transcription of Interferon-stimulated Genes by TNF-α and IFN-α Augments Antiviral Activity against HCV and HEV

Cited by 54 publications

References 39 publications

Nitazoxanide Inhibits Human Norovirus Replication and Synergizes with Ribavirin by Activation of Cellular Antiviral Response

Nitazoxanide Inhibits Human Norovirus Replication and Synergizes with Ribavirin by Activation of Cellular Antiviral Response

Slfn2 Regulates Type I Interferon Responses by Modulating the NF-κB Pathway

Identification of a TNF-α inducer MIC3 originating from the microneme of non-cystogenic, virulent Toxoplasma gondii

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