Original Research ARTICLE
Metabolic regulators Nampt and Sirt6 serially participate in the macrophage interferon antiviral cascade
- 1Cardiff University, United Kingdom
- 2University of Edinburgh, United Kingdom
- 3University of Veterinary Medicine Vienna, Austria
Molecular determinants underlying interferon (IFN)-macrophage biology can help delineate enzyme systems, pathways and mechanisms for enabling host-directed therapeutic approaches against infection. Notably, while the IFN antiviral response is known to be directly coupled to mevalonate-sterol biosynthesis pathway mechanistic insight for providing host pathway-therapeutic targets, remain incomplete. Here, we show that Nampt and Sirt6 are coordinately regulated upon immune activation of macrophages and contribute to the IFN-sterol antiviral response. In silico analysis of the Nampt and Sirt6 promoter regions identified multiple core immune gene-regulatory transcription factor sites, including Stat1, implicating a molecular link to IFN control. Experimentally, we show using a range of genetically IFN-defective macrophages that the expression of Nampt is stringently regulated by the Jak/Stat-pathway while Sirt6 activation is temporally displaced in a partial IFN-dependent manner. We further show that pharmacological inhibition of Nampt and small interfering RNA (siRNA)-mediated inhibition of Nampt and Sirt6 promotes viral growth of cytomegalovirus in both fibroblasts and macrophages. Our results support the notion of pharmacologically exploiting immune regulated enzyme systems of macrophages for use as an adjuvant-based therapy for augmenting host protective pathway responses to infection.
Keywords: Cholesterol, Metabolism, Lipid pathway, sterol, epigenetic, interferon, Cytomegalovirus
Received: 08 Oct 2018;
Accepted: 11 Feb 2019.
Edited by:Maria Laura Gennaro, Rutgers, The State University of New Jersey, Newark, United States
Reviewed by:Sandra M. Muxel, University of São Paulo, Brazil
Rodrigo T. Figueiredo, Federal University of Rio de Janeiro, Brazil
Copyright: © 2019 Dantoft, Robertson, Strobl and Ghazal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Peter Ghazal, Cardiff University, Cardiff, CF10 3AT, United Kingdom, email@example.com