Cellular NAD+ Levels Modulate the Immune Response to COVID-19

Immunity

Researchers propose that increasing NAD+ levels improves immune function in COVID-19 infection.

NAD+ is involved in multiple cellular reactions for the generation of energy and maintenance of cellular health, including immune responses to viral infections. Studies indicate cellular NAD+ levels diminish with age in people, and lower NAD+ levels associated with older age can adversely affect the immune response to infection, which includes the response to COVID-19. The death rates from COVID-19 increase with age, and for people above 80 years old, it passes 14%, which suggests an age-related dysfunction of the immune system.

(Omran & Almaliki, 2020 | Journal of Infection and Public Health)
Scientists from Bahrain published a proposal in the Journal of Infection and Public Health where they elaborated on the influence of a molecule called nicotinamide adenine dinucleotide (NAD+) in modulating the immune response to COVID-19. In their proposal, the researchers state that the COVID-19 infection can lead to depleted cellular NAD+ levels and that restoring NAD+ levels could decrease the severity of the body’s immune reaction to the infection to improve the condition of COVID-19 patients. They believe that understanding the immune response mechanisms in SARS-CoV-2 will make the development of therapeutic options for the infection possible.

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Research indicates that alterations in immune responses accompany aging, including a reduced ability of the immune system to protect against infectious diseases and the reduced efficacy of vaccines in older adult populations. Differences at the DNA level exist between older and younger people that may influence the immune response, namely the length of telomeres, which are the ends of chromosomes . As people age, their telomeres become shorter due to the cell’s inability to fully replicate the ends of chromosomes during cell divisions when cells proliferate. NAD+-dependent enzymes called sirtuins modulate telomere length, and decreased NAD+ levels affect sirtuin activity and are associated with short telomeres that induce cell death.

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NAD+ has a vital role in the body’s antiviral response. A large protein called poly-ADP ribose polymerase-1 (PARP-1) catalyzes the breakdown of NAD+ to perform its antiviral functions. With ADP-ribose, a component from NAD+ after its breakdown, PARP-1 tags the viral genome and inhibits the activation of viral gene programs. But the viral family that SARS-CoV-2 comes from Coronaviridae possesses a molecular mechanism to remove the ADP-ribose molecular tag, thus inhibiting the protective effect of PARP-1. This scenario results in excessive PARP-1 activation accompanied by an inflammatory response.

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The excessive PARP-1 activation and inflammatory response to SARS-CoV2 lead to disproportionate NAD+ consumption, facilitating further reductions in cellular NAD+ levels. This ultimately inhibits cellular energy production that requires NAD+, leading to energy depletion and cell death. Moreover, reduced NAD+ levels from excessive PARP-1 activity leads to reduced sirtuin 1 (SIRT1) activity, a protein involved in cellular health maintenance and aging.
(Omran & Almaliki, 2020 | Journal of Infection and Public Health) DNA damage associated with aging leads to activation of PARP-1, decreasing NAD+ levels. This scenario results in a decline in SIRT1 activity which facilitates increased inflammation and reduced mitochondrial function.

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“This process of PARP-1 overactivation can be reversed by exogenous NAD+ administration,” stated the team of researchers in their publication, referencing a method to combat against reduced NAD+ levels. The team goes on to say that NAD+ can modulate a protein complex, NF-KB, with a pivotal role in the inflammatory response to SARS-CoV-2 infection. They say NAD+ supplementation with subsequent PARP-1 inhibition prevents NF-KB activation, reducing the inflammatory response to SARS-CoV-2.

“We suggested the use of NAD+ as an immunomodulator for COVID-19 in older patients. Restoring normal NAD+ levels could decrease the severity of immune reaction in those patients and improve their clinical condition,” stated the team in their publication. They conclude that a thorough understanding of the immune response mechanisms against SARS-CoV-2 will contribute to the development of preventative and therapeutic strategies against the virus.

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