RT Journal Article
SR Electronic
T1 Coronavirus Infection and PARP Expression Dysregulate the NAD Metabolome: A Potentially Actionable Component of Innate Immunity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.17.047480
DO 10.1101/2020.04.17.047480
A1 Heer, Collin D.
A1 Sanderson, Daniel J.
A1 Alhammad, Yousef M.O.
A1 Schmidt, Mark S.
A1 Trammell, Samuel A.J.
A1 Perlman, Stanley
A1 Cohen, Michael S.
A1 Fehr, Anthony R.
A1 Brenner, Charles
YR 2020
UL http://biorxiv.org/content/early/2020/04/18/2020.04.17.047480.abstract
AB Over the past several decades, multiple coronaviruses (CoVs) have emerged as highly infectious, lethal viruses in humans, most notably in the pandemic outbreak of COVID-19, the disease caused by SARS-CoV-2. To date, there are no known therapeutic or preventative agents to target CoVs. Though age and comorbidities severely increase case fatality rates, the host factors that influence resistance or susceptibility to infection with highly pathogenic human CoVs are unknown. Innate immune responses to CoVs are initiated by recognition of double-stranded (ds) RNA and induction of interferon, which turns on a gene expression program that inhibits viral replication. Here we show that COVID-19 patient samples of SARS-CoV-2 conserve the invariant sequence of the CoV macrodomain, an ADP-ribosylhydrolase domain previously shown to counteract innate immunity to both mouse hepatitis virus (MHV), a model CoV, and SARS-CoV. RNA sequence analysis of cell lines, infected ferrets, and a deceased patient’s lung shows that a set of poly(ADP-ribose) polymerase (PARP) family members are induced by SARS-CoV-2 infection; 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. The data suggest that boosting cytoplasmic but not nuclear NAD+ may restore antiviral PARP functions to support innate immunity to CoVs and other viruses susceptible to PARP-mediated antiviral activity.Competing Interest StatementCharles Brenner is chief scientific adviser of ChromaDex and owns shares of ChromaDex stock. Other others declare no competing interests.