Innate Immunity: The Body’s Security Force
Innate immunity is the body’s first line of defense against infection which is why this powerful security system needs all the fuel it can get. One cellular energy carrier critical to this process is nicotinamide adenine dinucleotide (NAD+).
To Know Thyself
Every day, millions of pathogens from the air, our skin, and our guts try to penetrate the body’s defenses and wreak havoc. Fortunately, humans have evolved countless mechanisms to deter and destroy these invaders—most of which are part of the very broad category of “innate immunity [1].”
Once a virus enters a host cell, local replication occurs. This involves co-opting the host cell’s machinery and disrupting the cell’s normal processes of energy generation, breakdown of proteins, fats, and carbs, and gene regulation. Viral invaders also use this machinery to export newly produced viruses once replication is completed within the infected cell. This mechanism allows the virus to spread to other cells within the infected tissue, as well as to other target organs [2].
When all goes well, a powerful innate immune affront can help stop a virus in its tracks. But this powerful force to be reckoned with can also at times activate a storm of cytokines (important signaling molecules) which can cause powerful and damaging effects like fever, inflammation, and cell destruction [1].
This is why immunity is a tight-rope balancing act—it needs to be strong enough to ward off pathogens, yet precise enough not to hurt its host in the process. Those whose immunity is over-active, and fails to distinguish self from foe, can end up with auto-immune conditions such as inflammatory bowel disease, psoriasis, lupus and much more. Even worse, the inflammation that accompanies many of these conditions then predisposes the development of conditions such as cancer [3].
It is essential for immunity to “know thyself,” and innate immunity is paramount for doing just that.
There’s Nothing Innate About It
Innate immunity is called “innate” because everyone is born with it—much of it is encoded in the body by ancient genes inherited from long-gone ancestors [1].
Unlike “adaptive” immunity, which is built up over a lifetime of being exposed to germs (or vaccines), innate immunity has to figure out if something’s an invader without ever having seen it before. To do this, innate immunity uses pattern recognition receptors (PRR) to look for “patterns” in molecules that resemble those of invaders [1].
But innate immunity is much more than the archer on the castle wall-- it’s also the walls, the moat and the gatekeeper.
Innate immunity provides numerous physical barriers, such as mucus and other secretions in the lungs and gut that trap and inactivate pathogens and prevent them from invading.
Innate immunity also plays a gatekeeper, phagocytosing (or “eating-up”) questionable antigens and presenting them to T-cells to activate the adaptive immunity. The adaptive immunity then “learns” that specific pathogen and launches a targeted response, remembering the invader for the next time it tries to cause trouble. This is how vaccines work, and why for many infections, one exposure is all it takes to protect against any future infection [1].
Important ‘gatekeeper’ immune cells called macrophages reside within tissues and are a critical part of early innate defense mechanisms. Interestingly, macrophage activation is linked to reprogramming of several metabolic pathways. Maintaining appropriate levels of NAD+ and NADH is principal among these pathway alterations and ensures that appropriate energy-generating reactions are maintained as well as the activities of enzymes that rely on NAD+ for their function.
Macrophages often become depleted of NAD+ in response to inflammation and activation. As researchers have dug deeper into the cause for NAD+ depletion they’ve learned that expression of certain PARP enzymes (specifically PARP 3,4,9,10, and 12) increase within one hour of macrophage activation [4]. PARPs have long been known as major consumers of NAD+ [5].
In addition to PARPs, Sirtuins and CD38 are also known to consume NAD+ in later stages of inflammatory macrophage activation, further promoting NAD+ depletion [6,7].
With Great Power Comes Great Responsibility (and Expense)
Because the immune system is so powerful, it needs to be kept strictly in check, and also stay properly fueled and activated.
When this balance is disrupted, the immune response can become more damaging than the disease itself, like we’ve seen with the coronavirus pandemic. By setting off all immune cells, COVID infection can cause a cytokine storm, which is a massive release of those cytokines (like TNF alpha and IL-6) that ends up damaging the lungs and hurting more than it helps. This may explain why some COVID patients end up in the ICU with deadly acute respiratory distress syndrome caused by their immune systems [8].
Essential to the immune system’s success is finding that perfect balance between enough inflammation to kill the virus, but not so much to flood the lungs and endanger the host. The cellular energy molecule NAD+ plays the role of a mediator, upregulating protective enzymes called Sirtuins and decreasing pro-inflammatory signaling molecules like Nuclear factor kappa B to prevent the immune system from getting carried away [9-12].
Recent preclinical studies suggest that modulation of NAD+ levels is important to cell survival when innate immunity is activated [13, 14].
Modulating Innate Immunity with NAD+ and Its Precursors
Innate immunity is a jack of all trades, preventing, recognizing and combating invaders while keeping the immune response at bay. Maintaining proper NAD+ levels may be essential to empowering our immune system to do its job. The NAD+ precursor nicotinamide riboside (NR) is currently under investigation for its potential to support patients infected with COVID-19.
NR is a uniquely proven, safe, and effective means of raising cellular NAD+ levels. In preclinical models including cells and mice, NR has been demonstrated to activate the protective enzymes called Sirtuins [15, 16] and decrease levels of the proinflammatory factors IL-6 and TNF alpha [11]. In healthy older men, NR has been shown to decrease the levels of cytokines implicated in the body’s overzealous response to COVID [9-14].
More work is needed to assess how increased NAD+ levels may help support patients’ cellular resilience in the face of viral exposure. Additional investigations are currently under way, examining the impact of modulating NAD+ levels with nicotinamide riboside on the cellular response to Coronavirus infection. These results will inform the design of subsequent human clinical studies to better understand the role of NAD+ in support of the innate immune response, as well as in subsequent stages of viral infection.