Modulation of Host Immunity with Dietary Supplements Nicotinamide

National Heart, Lung, And Blood Institute

Investigators

Abstract

There is a continuing need to identify cost effective treatments for SARS-CoV-2 pneumonia. Nicotinamide (NAM) is the amide form of dietary niacin and precursor to NAD, a required cofactor in cellular function. We showed recently that NAM and its metabolites protect against excessive hypoxia induced factor-1a-associated inflammation and injury in human macrophages in vitro. Because HIF-1a activation has now been associated with SARS-CoV-2 inflammatory lung injury, we speculated that NAM would be an effective SARS-CoV-2 treatment. In a systematic review we conducted of 21 published animal studies, NAM treatment appeared to increase survival in infectious disease models but only one study included a virus challenge, SARS-CoV-2. While NAM potentially increased survival in this study, only 10 NAM and 10 control animals were investigated. However, across all published studies, quality of evidence was very low as no study provided a sample size assessment or blinding of outcome assessment, and almost all studies failed to randomize animals to treatment. We therefore did an initial randomized and blinded pilot study using our mouse hepatitis virus-1 (MHV-1, referred to as MHV) challenged A/J mouse model to examine the potential survival effects of NAM treatment. MHV is a beta-coronavirus like SARS-CoV-2 but can be studied at BSL-2 conditions. Intratracheal (IT) MHV challenge in our mouse model produces pneumonia and acute lung injury (ALI) that develops and then resolves over a 10 to 14d time-period that closely simulates the pathology and time course of SARS-CoV-2 pneumonia. A pilot study evaluating the effect of a 5-day regimen of NAM provided starting at the time of infection with MHV showed a potential benefit in the setting of a lethal MHV model. Based on our findings in human macrophages and the results of our systematic literature review and this in vivo pilot study, we hypothesize that NAM treatment will improve survival with MHV challenge producing a high lethality rate. We also hypothesize that treatment will be associated with increased tissue NAM and NAM metabolite levels and decreased tissue inflammation and hypoxia and lung injury in infected animals. Therefore, the goal of the present study is to prospectively test the effects of our pilot study NAM regimen in mice challenged with an MHV dose producing a high lethality rate. We will determine the optimal regimen of NAM producing desired cirulating and tissue levels of NAM and NAM metabolites. We will test the effects of this optimal regimen on survival in MHV-infected mice. We will finally study the mechanisms of the survival effects noted above.