Immunometabolic approaches to prevent, detect, and treat neonatal sepsis

Abstract

OL is a named inventor on several patents relating to vaccine adjuvants. Category of study: Review • Neonatal sepsis is a leading cause of early life mortality and there is an unmet need to address it. • Emerging evidence indicates that immunometabolism is relevant to the pathophysiology of neonatal sepsis, but much remains to be learned regarding its distinct features and regulation. • We discuss the interconnection of metabolism and immunity in early life and how distinct immunometabolism may be leveraged to improve prevention, diagnosis, and therapy of neonatal sepsis.

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

“…Changes in glucose, glutamine and cholesterol metabolism enable maintenance and longevity of trained immunity via accumulation of immunologically active intermediate metabolites (Fok et al, 2018). Examples include: (a) cholesterol, which participates in cell membrane remodeling and increased sensitivity to subsequent stimuli, (b) succinate and fumarate, which antagonize histone demethylation and suppress antiinflammatory genes, (c) acetyl-CoA, an essential substrate for acetylating processes, and (d) NAD + which is important for epigenetic changes resulting in a switch from glucose to fatty acid oxidation during LPS-induced tolerance and sepsis-induced immune paralysis (Conti et al, 2019). Immunometabolic changes may be different between newborns and adults, reflecting the differential nutritional and metabolic needs of the two groups, as well as their distinct immune response to pathogens (Kan et al, 2018;Dreschers et al, 2019).…”

“…Immunometabolic changes may be different between newborns and adults, reflecting the differential nutritional and metabolic needs of the two groups, as well as their distinct immune response to pathogens (Kan et al, 2018;Dreschers et al, 2019). Indeed the ontogeny of immunometabolism is an emerging and promising area of research (Conti et al, 2019) (see Box 2).…”

Integrative Metabolomics to Identify Molecular Signatures of Responses to Vaccines and Infections

“…The interplay between metabolism and the immune response is increasingly recognized, and distinct metabolic needs and demands define responses to infection and vaccination [50]. Immunometabolism is a rapidly evolving field of immunology, and the metabolites produced by leukocytes serve as potent immune signaling molecules, during primary (innate), trained (innate memory), and classical adaptive immunity [51]. Trained immunity, the phenomenon of antigen-agnostic memory responses by leukocytes subjected to various environmental threats, is an evolutionary process mediated by epigenetic modulations [52].…”

The Role of Microbiota in Neutrophil Regulation and Adaptation in Newborns

“…So far it is known that septic reactions in infants are accompanied by a heightened immune activity driven by neutrophils, an energy-demanding process that is mainly promoted by a shift of metabolism toward aerobic glycolysis, a similar process that trained cells undergo ( 142 – 144 ). In line with this, accumulation or activation of several metabolic intermediate products have been shown to either promote the induction of trained immunity (e.g., accumulation of fumarate) or tolerance (i.e., itaconate pathway) thus affecting also main cellular actions of neutrophils that may affect the innate immune response during infancy ( 94 , 97 ).…”