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Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity

By Collin D. Heer, Daniel J. Sanderson, Lynden S. Voth, Yousef M.O. Alhammad, Mark S. Schmidt, Samuel A.J. Trammell, Stanley Perlman, Michael S. Cohen, Anthony R. Fehr, Charles Brenner

Posted 18 Apr 2020
bioRxiv DOI: 10.1101/2020.04.17.047480

Innate immune responses are critical to control of viruses. Coronaviruses (CoVs) are positive strand RNA viruses with double-stranded RNA replication intermediates that are recognized by the innate immune system. Upon recognition, infected cells secrete interferon, which induces a set of interferon-stimulated genes that inhibit viral replication. Here we show that SARS-CoV-2 infection strikingly dysregulates the set of genes involved in consumption and biosynthesis of nicotinamide adenine dinucleotide (NAD). Highly induced genes include those encoding noncanonical poly(ADP-ribose) polymerase (PARP) family members known to function as mono ADP-ribosyltransferases but not known to deplete cellular NAD and genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR). We demonstrate that overexpression of PARP10 is sufficient to depress NAD levels and that the enzymatic activities of PARP10, PARP12 and PARP14 are limited by and can be enhanced by pharmacological activation of NAM salvage. We further showed that infection with the beta-coronavirus murine hepatitis virus (MHV) induces a severe attack on host cell NAD+ and NADP+. Finally we show that NAMPT activation, NAM and NR dramatically decrease replication in a MHV infection model that is sensitive to PARP activity. The data show that the antiviral activities of noncanonical PARP isozyme activities are limited by their own consumption of cellular NAD and that nutritional and pharmacological interventions to enhance NAD-based defenses may boost innate immunity. ### Competing Interest Statement CB is chief scientific adviser of ChromaDex and owns shares of ChromaDex stock. CB, SAJT, SP and ARF applied for a patent on uses of NAD boosting compounds to protect against CoVs. Others declare no competing interests.

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