Enhancing NAD+ levels May Boost Innate Immunity to Coronaviruses

Researchers suggest that supplementation with nutritional and pharmacological interventions like NR and NAM can combat coronavirus infection.

Coronavirus genomes, where the blueprint for building and assembling the virus is stored, do not encode enzymes needed for energy generation and synthesis of biological building blocks. These viruses depend on the exploitation of infected host cell functions for their assembly. The viral programs responsible for energy generation and the formation of chemical compounds that are encoded in the viral genome depend on the host’s nicotinamide adenine dinucleotide (NAD+) system, which is required for the functioning of many enzymes in the infected cells, such as those needed for antiviral defense. How the host NAD+ system and the enzymes that depend on it are hijacked for viral replication or employed as antiviral defenses are largely unexplored.

Heer and colleagues from the University of Iowa show in an article published in the Journal of Biological Chemistry that SARS-CoV-2 infection strikingly upregulates a subset of antiviral enzymes that depend on NAD+ called non-canonical Poly-ADP-ribose polymerases (PARPs) and induces the expression of genes encoding enzymes for NAD+ synthesis from NAD+ precursors nicotinamide riboside (NR) and a form of vitamin B3 called nicotinamide (NAM) but also downregulates other NAD+ biosynthetic pathways. They then show that supplementation with NR and NAM dramatically decreases the replication of a mouse coronavirus that is sensitive to PARP activity. These data suggest that nutritional and pharmacological interventions to enhance NAD+ levels may boost innate immunity to coronaviruses.

To get a better sense of the relationship between NAD+ and coronaviruses investigators analyzed SARS-CoV-2-infected human cell lines, a lung biopsy from people living with or dead from COVID-19, and bronchoalveolar lavage fluid from healthy individuals as well as those infected with COVID-19. Heer and colleagues show that SARS-CoV-2 infection turns on the genes encoding enzymes for salvage NAD+ synthesis from nicotinamide (NAM) and nicotinamide riboside (NR) while reducing the production of enzymes for other NAD+ biosynthetic pathways, such as those that utilize nicotinic acid (NA). The investigators showed that non-canonical PARP enzymes consistently have increased protein production by SARS-CoV-2 infections.

The research team from the University of Iowa shows that the activity of these non-canonical PARP enzymes is limited by cellular NAD+ and can be enhanced by pharmacological activation of NAD+ synthesis. They further demonstrate that infection with a mouse version of coronavirus induces a severe attack on host cell NAD+. These results presented warrant the testing of NAD+ boosting agents in the context of CoV infections. In addition to animal trials, the safety of various forms of vitamin B3 should allow rapid clinical assessments of NAD boosters to be evaluated.