Coronavirus Infection and PARP Expression Dysregulate the NAD Metabolome: A Potentially Actionable Component of Innate Immunity

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

Disease attributed to the current novel coronavirus (CoV) outbreak has rapidly spread globally, infecting 2 million people and killing more than 125,000 as of mid-April 2020 (Dong, Du, & Gardner, 2020) . The causative agent, severe acquired respiratory syndrome coronavirus 2, SARS-CoV-2, is transmitted largely by lipid droplets that infect cells of the lung epithelium (Wu, Wu, Liu, & Yang, 2020) . Like other positive strand RNA genome CoVs, SARS-CoV-2 replication proceeds through formation of double-stranded (ds) RNA , which elicits an interferon (IFN) response (Kindler, Thiel, & Weber, 2016; Totura & Baric, 2012) . A component of innate immunity that is expressed broadly and does not depend on professional cells of the acquired immune system, IFN-driven gene expression elicits responses that have largely evolved to arrest protein synthesis and other aspects of host metabolism on which the virus depends (Schoggins & Rice, 2011) . Specifically, CoV genomes do not encode enzymes needed for fuel oxidation, ATP generation, nucleotide, amino acid, lipid or protein synthesis, and therefore depend on exploitation of host functions to synthesize and assemble more viruses Zhu et al., 2020) . Accordingly, viral replication and host cell homeostasis both depend on the four nicotinamide adenine dinucleotide (NAD) coenzymes, NAD + , NADH, NADP + and NADPH, which are the central catalysts of metabolism (Belenky, Bogan, & Brenner, 2007) . These coenzymes accept and donate electrons in essential, ubiquitous processes of fuel oxidation, biosynthesis, and the generation and detoxification of reactive oxygen species.