Interplay between the immune response and the adaptation of metabolic pathways upon infection

Abstract Glucose is the principal metabolic fuel for the energy needs of most cell types. Upon infection, cytokines secreted by the immune system regulate redistribution of glucose to meet new metabolic needs associated with clearing the pathogen. We develop a mathematical model to describe the dynamics of such adaptation of metabolic pathways mediated by the immune response and its impact on the ability to clear pathogen and restore health. We find that cytokine-regulated redistribution of glucose resources in different tissues is critical for an effective immune response to pathogen as strictly clamping plasma glucose levels to homeostatic levels results in an ineffective immune response. By studying the effects of various parameters in our model, we describe how aberrant regulation of adaptation mechanisms affect outcomes of infection. Too high a glucose consumption rate by innate immune cells to mediate functions results in failure to clear pathogen. Pathogens with a very high replication rate can be controlled to low levels, but at a very high metabolic cost. Too low a pathogen replication rate allows the pathogen to hide from the immune system and rebound to high levels at later times. Finally, the strength of the innate immune response must be regulated to not be too high, not only to limit immunopathogenesis, but also for mediating an effective adaptive immune response. Competing Interest Statement A.K.C serves as a consultant for Flagship Pioneering, and its affiliated companies, Apriori Bio and Metaphore Bio. He is an ad hoc consultant for Dewpoint Therapeutics. A.K.C. has financial interests in the above companies. R.M. serves as a consultant for Foresite Labs and Nilo Therapeutics and has financial interest in these companies.