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

Based on ferret and human expression data in response to SARS-CoV-2 infection (Fig. 1) , approaches 1 and 2 are unlikely to be effective because they require expression of genes, such as QPRT, NADSYN and NAPRT (Bogan & Brenner, 2008) , that appear to be depressed by SARS-CoV-2 infection. NADSYN, which catalyzes the final step in NAD synthesis from trp and NA (Bieganowski, Pace, & Brenner, 2003) , is significantly depressed in the human lung while NAPRT is significantly depressed in the ferret trachea. It was interesting to note that the IDO1 gene and both the IDO1 and IDO2 genes are upregulated in the ferret and human infection samples, respectively. Without expression of the entire de novo biosynthetic pathway, these data suggest that infected cells are engaging kynurenine synthesis in 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, 1991) 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) Box 1 . CC-BY-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.17.047480 doi: bioRxiv preprint an inflammatory or immunomodulatory response to viral infection (Bessede et al., 2014) .