@HeerCollin @FehrLab @MichaelNADbio & I just published biorxiv.org/content/10.110…. This is our 1st of several works on #SARSCoV2. We show that the virus upsets the NAD system in powerful & potentially actionable ways /1
With my former student, Sam Trammell, we obtained data showing that coronaviruses upset cellular NAD. This is important because our cells need NAD coenzymes to run everything including our defense against viruses--the virus also hijacks our metabolism to make more virus /3
@HeerCollin decided to look at what we think is the entire set of genes controlling NAD metabolism as a function of SARSCoV2. We looked at 2 infected human lung cell lines, ferrets & a person who died of #COVID19 using RNA sequencing data that were provided by @virusninja /4
There's a set of so-called PARP genes that are profoundly upregulated by SARSCoV2 including PARP9, 11 & 13. These are not well known enzymes & their names are misnomers because they do not form poly(ADPribose) like PARP1 and PARP2 /5
These enzymes are actually monoADPribose transferases that use NAD to form ADPribose modifications on target proteins. @FehrLab focuses on these bc he showed that the virus's ADPribosylhydrolase & these enzymes do battle with each other /6
@MichaelNADbio focuses on these enzymes bc he loves NAD as much as I do & he developed tools to figure out what exactly these enzymes target when they get turned on by viral infection @MichaelNADbio @FehrLab @CharlesMBrenner #threeamigos /7
The infected cell turns on these genes as part of innate immunity--it detected virus & uses PARPs to try to shut down replication. The virus tries to shut down the innate immune defense with its ADPribosylhydrolase. It is cellular warfare & the battleground is NAD /8
So we looked at coronavirus-infected cells: infection knocks down their NAD and NADP by about 3-fold. We then asked can a PARP like the ones that are upregulated depress cellular NAD? We showed that yes, PARP10 overexpression knocks down NAD 2-fold /9
We then took advantage of a simple way to detect restored PARP10 activity & two methods to boost NAD. A NAMPT activator & a PARP1,2 inhibitor both restored cellular NAD but only the NAMPT activator boosted PARP10 activity /10
We think this is bc the PARP1,2 inhibitor protects NAD in the nucleus while increasing NAMPT restores NAD in the cytoplasm, where it is needed. This makes the PARP inhibitors used in cancer unlikely medicines for SARSCoV2 prevention & suggests that NAMPT activators be tested /11
The caveat is that NAMPT drives pulmonary vascular remodeling--ppl have proposed to inhibit this enzyme to improve lung health. NAMPT activators will go to animal trials, though, for SARSCoV2 prevention /12
What about NAD precursors? The gene expression data in our preprint say that it may be hard to increase NAD synthesis in infected cells through tryptophan or nicotinic acid. However, the NMRK1 & 2 genes for #NR usage and nicotinamide usage are upregulated by viral infection /13
This is an exciting result. Our labs are working hard under quite difficult conditions to follow this up in multiple ways. We suffered from 2 @fedex failures just this month. Our personnel work with face shields & #physicaldistancing to get the results out /14
Our groups will be determining how best to restore the NAD system & support PARP functions in innate immunity. Much work to be done but we wanted to get this body of work out to enable developments now that we know that coronaviruses initiate a tug-of-war over cellular NAD /end
