Is there a Link between NAD+ and the Cells’ Innate Immune Response?

NAD+ may hold the key to supporting cellular resilience in immune stress, such as viral infections.

From Energy To Immunity

Maintaining optimal health during this season is hard work as your cells require energy to help repair the damage caused by free radicals [1]. NAD+ is an essential coenzyme used in every step of this process, powering repair enzymes called sirtuins and PARPs [2-4].

Subduing A Virus

Many viruses first invade your cells long before any symptoms appear. In order to replicate and spread, it hijacks the cellular machinery, replicating itself millions of times.

Cells try to foil this plan with NAD-dependent enzymes like PARPs, but some viruses have evolved countermeasures, an enzyme called poly-ADP ribose glycohydrolase (PARG), to disable the immune response [5].

A cat and mouse game between host cell and virus ensues, draining your cells of NAD+. Initial tissue studies of infected human and animal lungs suggest the virus may even try to suppress your cells from producing more NAD+ [6, 7].

Recent studies suggest that some virus may even try to suppress the cells ability from producing more NAD+.  COVID-19 has been shown in a preclinical paper to deplete cellular NAD+ levels by more than three-fold, potentially weakening the cells’ resilience in turn [6, 7].

This type of essential immune cell is called a macrophage – NAD+ depletion has been linked to immune dysfunction [8].

Data suggests that maintaining cellular NAD levels, either by increasing its production or inhibiting its depletion may benefit the cells, but further study is required. COVID-19 seems to target high energy expenditure organs, like lungs, kidneys and intestines [9]—organs that require as much NAD+ as they can get.

The key to the immune system’s victory against virus’ such as COVID-19 is about finding that “goldilocks zone” between enough inflammation to kill the virus, but not so much to flood the lungs and endanger the host [11].

On top of its role in helping to fuel a robust, rapid response, NAD+ is believed to play something of a mediator, upregulating sirtuins, which can in turn help to keep pro-inflammatory signaling molecules at bay, helping calm the immune system [11].

Studies suggest that modulation of NAD+ levels may be important to cell survival when faced with the immune stress of something as serious as a COVID-19 infection [2, 12].

New preclinical tissue study showed that in COVID-19 infected cells, NAD+ levels are depleted, but the NRK pathway is upregulated, suggesting cells actively seek precursor elements in an attempt to replenish NAD+ levels when exposed to such immune stress [7].

REFERENCES

1. FILOMENI, G., D. DE ZIO, AND F. CECCONI, OXIDATIVE STRESS AND AUTOPHAGY: THE CLASH BETWEEN DAMAGE AND METABOLIC NEEDS. CELL DEATH DIFFER, 2015. 22(3): P. 377-88.
2. FEHR, A.R., ET AL., THE IMPACT OF PARPS AND ADP-RIBOSYLATION ON INFLAMMATION AND HOST-PATHOGEN INTERACTIONS. GENES DEV, 2020. 34(5-6): P. 341-359.
3. VACHHARAJANI, V.T., ET AL., SIRTUINS LINK INFLAMMATION AND METABOLISM. J IMMUNOL RES, 2016. 2016: P. 8167273.
4. MESQUITA, I., ET AL., EXPLORING NAD+ METABOLISM IN HOST-PATHOGEN INTERACTIONS. CELL MOL LIFE SCI, 2016. 73(6): P. 1225-36.
5. ALHAMMAD, Y.M.O. AND A.R. FEHR, THE VIRAL MACRODOMAIN COUNTERS HOST ANTIVIRAL ADP-RIBOSYLATION. VIRUSES, 2020. 12(4).
6. BLANCO-MELO, D., ET AL., SARS-COV-2 LAUNCHES A UNIQUE TRANSCRIPTIONAL SIGNATURE FROM IN VITRO, EX VIVO, AND IN VIVO SYSTEMS. BIORXIV, 2020: P. 2020.03.24.004655.
7. HEER, C.D., ET AL., CORONAVIRUS INFECTION AND PARP EXPRESSION DYSREGULATE THE NAD METABOLOME: A POTENTIALLY ACTIONABLE COMPONENT OF INNATE IMMUNITY. BIORXIV, 2020: P. 2020.04.17.047480.
8. MINHAS, P.S., ET AL., MACROPHAGE DE NOVO NAD(+) SYNTHESIS SPECIFIES IMMUNE FUNCTION IN AGING AND INFLAMMATION. NAT IMMUNOL, 2018.
9. KOUHPAYEH, S., ET AL., THE MOLECULAR STORY OF COVID-19; NAD+ DEPLETION ADDRESSES ALL QUESTIONS IN THIS INFECTION. PREPRINTS, 2020.
10. SHI, Y., ET AL., COVID-19 INFECTION: THE PERSPECTIVES ON IMMUNE RESPONSES. CELL DEATH DIFFER, 2020.
11. WANG, X., ET AL., SIRTUINS AND IMMUNO-METABOLISM OF SEPSIS. INT J MOL SCI, 2018. 19(9).
12. LIU, P., ET AL., SIRTUIN 3-INDUCED MACROPHAGE AUTOPHAGY IN REGULATING NLRP3 INFLAMMASOME ACTIVATION. BIOCHIM BIOPHYS ACTA MOL BASIS DIS, 2018. 1864(3): P. 764-777