Metabolic Regulators Nampt and Sirt6 Serially Participate in the Macrophage Interferon Antiviral Cascade

Abstract

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, 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.

CD38 in the age of COVID-19: a medical perspective

“…Sirtuins are dependent on NAD 1 biogenesis, and thus regulated by Trp or by nicotinamide phosphatidyltransferase (NAMPT), the rate-limiting enzyme that converts NAM into NAD 1 (FIGURE 4). Sirtuins and NAMPT participate in macrophage antiviral activity (116). In addition, CD38 activates the Sirtuin/NF-κB pathway in a NAD 1dependent manner, since CD38 blocking increases NAD 1 levels and Sirtuin-1 activity in the nuclear, cytoplasmic, and mitochondrial compartments (26,117).…”

Immunometabolic Status of COVID-19 Cancer Patients

“…In MERS-CoV patients, the severity of lung lesions has been shown to correlate with extensive infiltration of neutrophils and macrophages within the lungs and in peripheral blood ( 60 ). In support of a central role of NAD + metabolism in myeloid cells, the IFN-induced antiviral cascade operated by macrophages utilizes the metabolic regulators NAMPT and Sirt6 serially ( 18 ). In addition, extracellular (e)NAMPT can behave as alarmin or damage-associated molecular pattern (DAMP) and has been found to be elevated in patients with comorbidities including diabetes, obesity, and cancer ( 3 ) that worsen patient frailties to SARS-CoV-2, while it marks sepsis and septic shock.…”

“…In this contest, iNAMPT was recently identified as a critical modulator of immunometabolism and mobilization of M2-polarized anti-inflammatory myeloid cells to the periphery in cancer bearers ( 80 ). Furthermore, NAMPT metabolism participates in macrophage antiviral activity ( 18 ), hence highlighting its potential relevance in the surveillance of homeostatic and immune functions exercised by alveolar and interstitial macrophages. Preexisting antiviral response might suppress antibacterial Th17 via IFN-induced IL-23 downregulation ( 12 ), an effect that can be surpassed by the indiscriminate lymphopenia occurring along disease progression.…”

In vitro analysis of the renin–angiotensin system and inflammatory gene transcripts in human bronchial epithelial cells after infection with severe acute respiratory syndrome coronavirus

“…IFNB1 deficiency results in partial suppression of the sterol pathway in macrophages during viral infections, thereby associating the regulation of the lipid metabolism pathway with interferon antiviral defense responses. 38 Furthermore, NK cells are important in immune defense against virus infections. Enlarged virus replication and more serious diseases during encephalomyocarditis virus, Coxsackie virus, and Theiler's murine encephalitis virus infections are linked with the reduction of NK cells or low levels of NK cell cytolytic function.…”