The Modulation of Cholesterol Metabolism Is Involved in the Antiviral Effect of Nitazoxanide.

Claudio Fenizia,Sergio Strizzi,Daria Trabattoni,Jean-François Rossignol,Claudia Vanetti,Salomè Valentina Ibba,Mario Clerici,Mara Biasin

doi:10.3390/idr13030060

Claudio Fenizia, Sergio Strizzi + Show 6 more

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https://doi.org/10.3390/idr13030060

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Abstract

We previously investigated the role of Nitazoxanide (NTZ), a thiazolide endowed with antiviral and antiparasitic activity, in HIV-1 infection. NTZ treatment in primary isolated PBMCs was able to reduce HIV-1 infection in vitro by inducing the expression of a number of type-I interferon-stimulated genes. Among them, NTZ was able to induce cholesterol-25-hydroxylase (CH25H), which is involved in cholesterol metabolism. In the present study, we wanted to deepen our knowledge about the antiviral mechanism of action of NTZ. Indeed, by inducing CH25H, which catalyzes the formation of 25-hydroxycholesterol from cholesterol, NTZ treatment repressed cholesterol biosynthetic pathways and promoted cholesterol mobilization and efflux from the cell. Such effects were even more pronounced upon stimulation with FLU antigens in combination. It is already well known how lipid metabolism and virus replication are tightly interconnected; thus, it is not surprising that the antiviral immune response employs genes related to cholesterol metabolism. Indeed, NTZ was able to modulate cholesterol metabolism in vitro and, by doing so, enhance the antiviral response. These results give us the chance to speculate about the suitability of NTZ as adjuvant for induction of specific natural immunity. Moreover, the putative application of NTZ to alimentary-related diseases should be investigated.

Highlights

NTZ was shown to inhibit in vitro HIV-1 replication and to upregulate the expression of proteins that are involved in cholesterol metabolism and efflux, such as cholesterol-25-hydroxylase (CH25H) and liver X receptor (LXR) [11], as well as those encoding lipid-transport proteins, such as the ATP-binding cassettes A1 (ABCA1) and
Because IFNα and IFNβ are responsible for the induction of the transcription of interferon-stimulated genes (ISGs), and in particular of CH25, a protein endowed with antiviral properties, we initially verified whether exposure of peripheral blood mononuclear cells (PBMCs) to NTZ did upregulate CH25H transcription
The addition of NTZ to PBMC cultivated in medium alone modestly increased CH25H

Summary

Introduction

Nitazoxanide (Alinia® , NTZ), a compound initially used as an anti-parasitic agent, was shown to be effective against many DNA and RNA viruses, including Influenza virus, HCV and HBV [1,2,3,4,5,6,7,8,9,10]. NTZ was shown to inhibit in vitro HIV-1 replication and to upregulate the expression of proteins that are involved in cholesterol metabolism and efflux, such as cholesterol-25-hydroxylase (CH25H) and liver X receptor (LXR) [11], as well as those encoding lipid-transport proteins, such as the ATP-binding cassettes A1 (ABCA1) and. There is an increasing body of literature showing a tight connection between immune inflammatory processes and sterol metabolism, including cholesterol transport, storage and excretion [12,13]. Interferons (IFNs), one of the most potent anti-viral signaling molecules, simultaneously trigger a broad response by upregulating hundreds of interferon-stimulated genes (ISGs) [14,15]; among such ISGs, CH25H was identified as a

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