Blackmores Institute

Publishing in The FEBS Journal, the authors advocate for a new looking at sepsis, shifting the focus from the pathogen itself to the host immune and metabolic responses.“Sepsis, not to be confused with ‘septicaemia’ (bloodstream infection), is a life-threatening organ dysfunction condition caused by the body’s own dysregulated response to infection. Sepsis can be triggered by diverse pathogens and non-infectious insults. Why some people succumb to sepsis from triggers such as influenza or SARS-CoV-2 infection, while others have a mild or asymptomatic infection is unknown.“While many eyes focus on the pathogen itself, a closer look at host immune and metabolic responses to diverse pathogens is critical. Avenues of investigation from both ageing research and immunology are converging attention on a pathway, which connects immune responses with ageing,” the authors explained.According to the authors, the essential role of nicotinamide adenine dinucleotide (NAD+) in cellular energy metabolism, links to healthy ageing and proteins associated with longevity as well as advances in immunology suggest that de novo production of nicotinamide, a precursor to NAD+ is a central pathway upregulated in many infectious diseases.“In the macrophage, a central mediator of immune responses, de novo NAD+ synthesis was required to maintain an ‘anti-inflammatory homeostatic state with robust phagocytic capacity’. We propose that sepsis due to SARS-CoV-2 or other viral or bacterial infections is caused by pathogens interfering with host NAD metabolism. Elderly individuals, or those with pre-existing diseases, may already have certain aberrations in their NAD metabolic pathways that predispose them to more severe disease,” the authors said.Drawing on an evolutionary perspective to understand how macrophage or lymphocyte metabolic shifts correlate with infection by a ‘foreign’ micro-organism, the authors suggest that mitochondrial sensing of double-stranded RNA, or other mitochondrial patterns, or other mitochondrial identifiers increase the cellular requirement for NAD+. This prompts an increased tryptophan conversion to nicotinamide via indoleamine 2,3-dioxygenase (IDO) activation.“In humans, nicotinamide is acquired from dietary sources as vitamin B3 and subsequently recycled through existing nicotinamide pools. Alternatively, nicotinamide may be synthesized de novo from the amino acid tryptophan. The rate-limiting enzyme for de novo nicotinamide synthesis is IDO found predominantly in cells of the macrophage/monocyte lineage.“Macrophages have long been described as able to become activated in one of two ways, simplistically thought of as ‘pro-inflammatory’ and ‘anti-inflammatory’ or termed by ‘M1’ and ‘M2’ nomenclature. M2 macrophages express IDO, which diverts tryptophan to de novo synthesis of nicotinamide rather than towards serotonin synthesis. IDO-mediated tryptophan catabolism in turn depresses T-cell proliferation and stimulates regulatory T cells, which are cells with immune suppressive function,” the authors explained.If the primary pathology is competition for depleted NAD+ stores, the authors suggest the most rational intervention would be to increase NAD+ supply. The leading candidate for investigation for the treatment of sepsis, including COVID-19, should therefore be nicotinamide (Vitamin B3) and related compounds,“Nicotinamide has been used for a multitude of clinical indications, including lung diseases. The stalwart of antituberculosis therapy, isoniazid, was initially developed as a nicotinamide analogue, but showed superior performance compared with nicotinamide for clinical outcome in tuberculosis.“In summary, we advocate adjusting our understanding of pathogenesis of infectious illness away from a microbe-oriented view, such that the microbe is seen as ‘causing’ the disease, towards a host NAD–metabolism-oriented view, where the microbe is seen as triggering an evolutionarily conserved response that shifts NAD metabolism. In certain contexts, such as during reproduction, shifts in NAD metabolism may be beneficial for the organism,” the authors said.The report concluded that vitamin B3 was being investigated as a therapy for sepsis, including that caused by COVID-19, ideally as a single agent at high dose rather than within a multivitamin. Source:
 Suchard MS, et.al.: Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts. The FEBS Journal. March 2021 <a href="https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.15807" target="_blank">doi:10.1111/febs.15807</a>

Researchers are calling for a new way of understanding the pathogenesis of infections suggesting that vitamin B3 (nicotinamide) and analogues be evaluated as a therapy for infectious causes of sepsis including COVID-19.

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