# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 4 Infection Treatment and Immunomodulatory Effects  
NAD\({}^{+}\) intermediates have been recognized for their beneficial health effects during infection with several pathogens. Studies have confirmed antimycobacterial effect of NAM in patients infected with _Mycobacterium tuberculosis_[121; 122], while immune-mediated elimination was reported for _Staphylococcus aureus_, including MRSA and other major human pathogens such as _Klebsiella pneumoniae_ and _Pseudomonas aeruginosa_[123]. In addition, NAM and its analogues exhibited antiviral effect in patients with HIV [121] and hepatitis B [124]. The potential treatment with NAD\({}^{+}\) intermediates has been recognized recently for combating COVID-19 infection that currently lacks efficient therapeutic or preventive agents and represents a global concern for public health. SARS-CoV-2 infection triggers a maladaptive immune response. Notably an exaggerated proinflammatory response leading to a \"cytokine storm\" in the lung tissue, and lymphopenia with a drastic decline of CD4+ and CD8+ T cells [125]. On the molecular level, as the innate immune response activates to fight the infection, the activation of PARPs increases due to extensive DNA damage and IFN-induced MARylation (mono-ADP-ribosylation) of the target SARS-CoV-2 proteins [126; 127]. PARPs response is required for inhibition of viral replication [128]; however, this antiviral effect is reversed by the ADP-ribosylhydrolase macrodomain of the viral nonstructural protein, nsp3, whose activity is required for virulence [126; 127; 129]. In addition, nsp10 of SARS-CoV was found to inhibit electron transport at the NADH site of complex I in the mitochondrial electron transport chain [130], suggesting that key events in the innate immune response to viral infections are occurring within the infected cell's NAD\({}^{+}\) metabolome [131]. Recent study investigated PARPs expression and NAD\({}^{+}\) metabolome dysregulation due to coronavirus infection. The examined SARS-CoV-2 infected cell lines of a ferret and deceased patients' lungs showed disturbed NAD\({}^{+}\) metabolism and gene expression with respect to synthesis and utilization of NAD\({}^{+}\)[131]. Furthermore, the expression of the NMRK1 pathway was upregulated together with the expression of the concentrative nucleoside transporter CNT3, indicating a higher capacity for NR conversion to NAD\({}^{+}\) and NADP\({}^{+}\) during the infection [10]. An upregulation of the NMRK gene was previously associated with therapeutic efficacy of NR [66; 105]. In addition, the expression of NNMT (nicotinamide N-methyltransferasease) was decreased [131] due to lower NAM methylation, suggesting a promotion of the NAM salvage pathway [132] and increased efficiency of NR treatment to replenish NAD\({}^{+}\)[131]. These data indicate that boosting NAD\({}^{+}\) content through NAM and NR kinase pathways may restore antiviral PARPs functions to support innate immunity to SARS-CoV-2 [131]. Upon activation of the adaptive immune response, the overexpression of CD38 in both CD4+ and CD8+ lymphocytes further exaggerates NAD\({}^{+}\) depletion [133; 134] leading to increased production and release of proinflammatory cytokines, reactive oxygen species, and macrophage infiltration [135; 136]. Furthermore, drastic NAD\({}^{+}\) depletion impairs the function of sirtuins, the regulators of cell death and viability [133]. Specifically, SIRT1 regulates the expression of genes including tumor suppressors, cytokines and proto-oncogenes and ultimately modulates inflammation, cell survival, and apoptosis mechanisms [137]. Loss of sirtuin function along with increased oxidative damage and an overall energy decrease finally culminates in cell death. Replenishment of NAD\({}^{+}\) body content could restore energy levels and impaired sirtuin function and possibly rebalance the maladaptive immune response to SARS-CoV-2 infection.