https://www.biorxiv.org/content/what-un ... d-preprint"Readers should therefore be aware that articles on bioRxiv have not been finalized by authors, might contain errors, and report information that has not yet been accepted or endorsed in any way by the scientific or medical community."
Coronavirus Infection and PARP Expression Dysregulate the NAD Metabolome: A Potentially Actionable Component of Innate Immunity
Here we show that SARS-CoV-2 infection of cell lines, infected ferrets, and a deceased patient's lung consistently and strikingly dysregulates the nicotinamide adenine dinucleotide (NAD+) gene set with respect to NAD+ synthesis and utilization.
SARS-CoV-2 induces a set of poly(ADP-ribose) polymerase (PARP) family members; these PARPs include enzymes required for the innate immune response to MHV. Further, we show that MHV infection induces an attack on host cell nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+).
The data indicate that overexpression of a virally induced PARP, PARP10, is sufficient to depress host cell NAD metabolism and that NAD+ boosting strategies differ in their efficacy to restore PARP10 function.
Gene expression and pharmacological data suggest that boosting NAD+ through the nicotinamide and nicotinamide riboside kinase pathways may restore antiviral PARP functions to support innate immunity to SARS-CoV-2, whereas PARP1,2 inhibition may be less likely to restore antiviral PARP functions.
Major approaches to boost and/or maintain NAD coenzyme when the NAD system is under attack
1) Increase activity of the de novo biosynthetic pathway by inhibiting α-amino-β-carboxymuconateε-semialdehyde decarboxylase (ACMSD) (Katsyuba et al., 2018)
2) Increase the Preiss Handler biosynthetic pathway by supplementing with NA (DiPalma & Thayer,
3) Increase the NAM salvage pathway by supplementing with NAM (A. C. Chen et al., 2015)
4) Increase the NR salvage pathway by supplementing with NR (Bieganowski & Brenner, 2004)
5) Increase the NAM salvage pathway by activating NAMPT (Gardell et al., 2019)
6) Increase NAM salvage by inhibiting NNMT (Neelakantan et al., 2019)
7) Inhibit PARP1,2-dependent NAD+ consumption (Donawho et al., 2007)
8) Inhibit CD38-dependent NAD+ consumption (Aksoy, White, Thompson, & Chini, 2006)
Though the focus of this preclinical work is prevention, we note that innate immune responses to CoV infection, like other inflammatory responses, are potentially pathological if infection is not controlled. COVID-19 patients with acute respiratory distress syndrome experience a cytokine storm that features high level circulation of inflammatory cytokines (Mehta et al., 2020).
Interestingly, in a small placebo-controlled clinical trial designed to address the oral safety and activity of Niagen NR in older men, it was discovered that 1 gram of NR per day depresses levels of IL-6, IL-5, IL-2 and tumor necrosis factor alpha (Elhassan et al., 2019), suggesting the possibility that Niagen and other NAD boosters may also be tested for safety, control of cytokine storm, and modulation of COVID-19 disease in patients.
Competing Interest Statement
Charles Brenner is chief scientific adviser of ChromaDex and owns shares of ChromaDex stock.
https://www.biorxiv.org/content/10.1101 ... 2.full.pdf