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Coronavirus and PARP expression dysregulate the NAD Metabolome: a potentially actionable component of innate immunity

View ORCID ProfileCollin D. Heer, View ORCID ProfileDaniel J. Sanderson, View ORCID ProfileYousef M.O. Alhammad, View ORCID ProfileMark S. Schmidt, View ORCID ProfileSamuel A.J. Trammell, View ORCID ProfileStanley Perlman, Michael S. Cohen, View ORCID ProfileAnthony 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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  • For correspondence: arfehr@ku.edu charles-brenner@uiowa.edu
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Abstract

SARS-CoV-2 is a coronavirus (CoV) and cause of COVID-19, which is much more lethal in older people and those with comorbid conditions for unknown reasons. Innate immune responses to CoVs are initiated by recognition of double-stranded RNA and induction of interferon, which turns on a gene expression program that inhibits viral replication. Here we show that SARS-CoV-2 infection of cells, ferrets and a person strikingly dysregulates the NAD gene set by inducing a set of PARP family members that includes enzymes required for the innate immune response to CoVs. CoV infection also induces a severe attack on host cell NAD. Overexpression of one induced enzyme, PARP10, is sufficient to depress host NAD. Gene expression and pharmacological data suggest that boosting NAD through the nicotinamide and nicotinamide riboside kinase pathways may restore antiviral PARP functions to support innate immunity to CoVs, whereas PARP1,2 inhibition does not restore PARP10 activity.

Impact statement Specific disturbances in the NAD gene set, NAD metabolome and PARP activity were discovered as a defining feature of coronavirus infection that may lead to methods to boost innate immunity.

Competing Interest Statement

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

Footnotes

  • We added data from a new cell type to Figure 2 and updated the corresponding Supplemental information file.

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 30, 2020.
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Coronavirus 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 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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