What is the Link Between NAD+ and Your Cells’ Innate Immune Response?
Just like our planet is mustering up the resources to fight the ongoing COVID-19 (Coronavirus) pandemic, so too do our cells need energy to support cellular repair. NAD+ may hold the key to supporting cellular resilience in the face of immune stress, like viral infections. Newly published preclinical research from ChromaDex Chief Scientific Advisor Dr. Charles Brenner and his fellow investigators deepens our understanding of this important molecule.
From Energy to Immunity
Maintaining your health in the face of a virus like COVID-19 is hard work on your cells which require the energy to help repair the damage caused by free radicals [1]. NAD+ is essential to every step of this process, powering repair enzymes called sirtuins and PARPs [2-4].
Subduing a Virus
Like many viruses, COVID-19 first invades your cells long before you see any symptoms. In order to replicate and spread, it needs to hijack your cellular machinery to make millions of copies of itself.
Your cells try to foil this plan with NAD-dependent enzymes like PARPs, but COVID has evolved its own countermeasure, 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].
Results from Dr. Brenner’s recent preclinical study showed that COVID-19 depleted cellular NAD+ levels by more than three-fold, potentially weakening cells’ resilience in turn [7].
In fact, in a type of essential immune cell called a macrophage, NAD+ depletion has been linked to immune dysfunction [8].
In order to mount a powerful response when first faced with the new COVID-19 virus, data suggests that strategies to maintain cellular NAD levels, either by increasing its production or inhibiting its depletion may benefit your cells, but further study is required. COVID-19 seems to target high energy expenditure organs, like lungs, kidneys and intestines [9]—organs that need all the NAD+ they can get.
Managing the Cytokine Storm
While the initial immune counterattack is crucial, maintaining a proportional response as the infection evolves is equally important, yet challenging. By setting off all your immune cells, the later stages of a COVID-19 infection are often associated with what is known as a “cytokine storm,” which is a massive release of pro-inflammatory molecules that ends up damaging the lungs [10]. This may explain why some COVID-19 patients are asymptomatic, while others end up in the ICU with deadly acute respiratory distress syndrome [9].
The key to the immune system’s victory against 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 fueling a robust and rapid response, NAD+ is believed to play something of a mediator, upregulating sirtuins, which in turn help keep pro-inflammatory signaling molecules at bay to help calm the immune system from getting carried away [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].
Strategies to maintain cellular NAD+
Knowing NAD’s importance to overall cellular health, repair and resilience, maintaining its levels in the face of an immune stress becomes critical. Approaches to accomplish this include inhibiting its depletion in the cell or boosting its production with a NAD+ precursor, such as nicotinamide riboside.
Dr. Brenner’s 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 nicotinamide riboside in an attempt to replenish NAD+ levels when exposed to such immune stress [7].
Exciting times are ahead, as future research aims to understand the effect of boosting NAD+ with nicotinamide riboside on cells’ innate response to immune stress
References
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Minhas, P.S., et al., Macrophage de novo NAD(+) synthesis specifies immune function in aging and inflammation. Nat Immunol, 2018.
Kouhpayeh, S., et al., The Molecular Story of COVID-19; NAD+ Depletion Addresses All Questions in this Infection. Preprints, 2020.
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