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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, View ORCID ProfileCharles Brenner
doi: https://doi.org/10.1101/2020.04.17.047480
Collin D. Heer
aFree Radical and Radiation Biology Program, University of Iowa, United States
bDepartment of Biochemistry, University of Iowa, United States
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Daniel J. Sanderson
cDepartment of Chemical Physiology & Biochemistry, Oregon Health Sciences University, United States
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Yousef M.O. Alhammad
dDepartment of Molecular Biosciences, University of Kansas, United States
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Mark S. Schmidt
bDepartment of Biochemistry, University of Iowa, United States
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Samuel A.J. Trammell
bDepartment of Biochemistry, University of Iowa, United States
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Stanley Perlman
eDepartment of Microbiology & Immunology, University of Iowa, United States
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Michael S. Cohen
cDepartment of Chemical Physiology & Biochemistry, Oregon Health Sciences University, United States
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Anthony R. Fehr
dDepartment of Molecular Biosciences, University of Kansas, United States
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  • For correspondence: arfehr@ku.edu charles-brenner@uiowa.edu
Charles Brenner
bDepartment of Biochemistry, University of Iowa, United States
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  • ORCID record for Charles Brenner
  • For correspondence: arfehr@ku.edu charles-brenner@uiowa.edu
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Abstract

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 Statement

Charles Brenner is chief scientific adviser of ChromaDex and owns shares of ChromaDex stock. Other others declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 18, 2020.
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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
bioRxiv 2020.04.17.047480; doi: https://doi.org/10.1101/2020.04.17.047480
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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
bioRxiv 2020.04.17.047480; doi: https://doi.org/10.1101/2020.04.17.047480

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