NAD+ in COVID-19 and viral infections

Abstract

NAD⁺, as an emerging regulator of immune responses during viral infections, may be a promising therapeutic target for coronavirus disease 2019 (COVID-19). In this Opinion, we suggest that interventions that boost NAD⁺ levels might promote antiviral defense and suppress uncontrolled inflammation. We discuss the association between low NAD⁺ concentrations and risk factors for poor COVID-19 outcomes, including aging and common comorbidities. Mechanistically, we outline how viral infections can further deplete NAD⁺ and its roles in antiviral defense and inflammation. We also describe how coronaviruses can subvert NAD⁺-mediated actions via genes that remove NAD⁺ modifications and activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Finally, we explore ongoing approaches to boost NAD⁺ concentrations in the clinic to putatively increase antiviral responses while curtailing hyperinflammation.

Keywords: COVID-19; NAD(+); immune responses; inflammation.

Figure 1

NAD⁺ metabolism and points of pharmacological intervention. Enzymes involved in NAD⁺ biosynthesis and hydrolysis play important roles in inflammation and immunity. Biosynthetic pathways include the NAD⁺ salvage pathway, which recycles nicotinamide to form NMN, then NAD⁺, and the de novo pathway that begins with tryptophan. Hydrolysis of NAD⁺ is largely carried out by PARPs, which tag target proteins with poly- or mono-(ADP ribose); sirtuins, which remove acyl groups and create O-acyl-ADP-ribose; and CD38, BST, and SARM1, which create (cyclic)-ADP-ribose [44]. There are multiple points of potential pharmacological intervention throughout NAD⁺ metabolic pathways. Created with BioRender.com. Abbreviations: i, inhibitor; NAMPT, nicotinamide phosphoribosyltransferase; NMN, nicotinamide mononucleotide; NR, nicotinamide ribose; NSP3, nonstructural protein 3; PARP, poly(ADP-ribose) polymerase; SARM1, sterile alpha and TIR motif containing 1; SIRT, sirtuin.

Figure 2

Regulation of the NLRP3 inflammasome by SARS-CoV infection and NAD⁺. Several proteins encoded by SARS-CoV promote NLRP3 inflammasome activity and the release of proinflammatory cytokines. ORF3a activates NF-κB through TRAF3-dependent ubiquitination, which facilitates ASC speck formation and the assembly of NLRP3 inflammasome [86]. ORF3a also has transmembrane domains and ion channel activity that drives a K⁺ efflux [85]. E protein is located at the ER–Golgi compartment and promotes Ca²⁺efflux [87,88]. ORF8bdirectly interacts with NLRP3. These mechanisms all activate the inflammasome [89]. Host cell SIRT1, SIRT2, and SIRT3 all suppress the NLRP3 inflammsome [94., 95., 96., 97., 98.]. SIRT1 deacetylates NF-κB, suppressing its activity, and reduces oxidative stress, decreasing inflammasome activation. SIRT2 deacetylates NLRP3. SIRT3 suppresses mitochondrial ROS production, decreasing inflammasome activation. SIRT6 reduces inflammation via H3K9 deacetylation in the promoters of NF-κB target genes [99]. PARPs promote antiviral SG formation through ADP-ribosylation of SG components [71., 72., 73.]. Created with BioRender.com. Abbreviations: Ac, acetylation; ACE-2, angiotensin-converting enzyme 2; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain Casp1, caspase-1; ER, endoplasmic reticulum; NF-κB, nuclear factor κB; NLRP3, NOD-, LRR-, and pyrin domain-containing protein 3; ORF, open reading frame; SARS-CoV, severe acute respiratory syndrome coronavirus 1; SIRT, sirtuin; TRAF3, TNF receptor-associated factor 3; Ub, ubiquitination.