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

Here we show that SARS-CoV-2 infected tissue culture cells, ferrets and a deceased human victim of COVID-19 indicate that viral infection induces high level expression of multiple PARP isozymes including many of the same PARPs induced by MHV infection of BMDMs. SARS-CoV-2 infection of ferrets and the human also appears to down-regulate synthesis of NAD from tryptophan and nicotinic acid (NA) while upregulating synthesis capacity from nicotinamide (NAM) and nicotinamide riboside (NR). We also show that MHV infection results in a significant depression of key cellular NAD metabolites and that PARP overexpression is sufficient to depress NAD metabolism in a manner that resembles MHV infection. Whereas multiple approaches exist to restore NAD, we show that NAMPT activation but not PARP1,2 inhibition supports increased PARP10 enzymatic activity. The data justify further analysis of how nutritional and therapeutic modulation of NAD status may potentially restrict viral infection by boosting innate immunity.