Harnessing nutrition to enhance vaccine responses - PROJECT ABSTRACT Novel pathogens (e.g., SARS-CoV2, monkeypox, respiratory syncytial virus, and influenza) are constantly emerging, creating an urgent, unmet need to identify strategies that enhance immunological memory. Our previous work demonstrated that caloric restriction (CR) is a nutritional intervention that enhances immunological memory in mice, resulting in 500-fold greater pathogen control (Collins N, Cell, 2019 and Han SJ…Collins N*, PNAS, 2023). However, the molecular determinants, signaling pathways, and cell-cell interactions involved are unknown. The objective of this proposal is to generate fundamental mechanistic information that fills these gaps in knowledge, which will advance the field and ultimately reduce the burden of infectious diseases by (i) revealing how CR can be utilized to enhance pathogen- and vaccine-elicited immunological memory, and (ii) leading to the development of novel therapies that pharmacologically mimic the immune-enhancing effect of CR. Our recent publication indicated that CR enhances immunity by increasing memory CD8+ T cell-derived IFN and gut microbiota-derived acetate, which converge on myeloid cells to enhance their capacity to kill pathogens. Our preliminary metabolomics data first show that CR potently modulates systemic nutrient abundance. Memory CD8+ T cells metabolically adapt by switching their intracellular signaling pathways to promote the utilization of nutrient sources that are abundant in this setting, as shown by preliminary single-cell RNA-seq and flow cytometry results. The metabolic state adopted by memory T cells during CR has been shown to enhance their function, providing a potential explanation for increased IFN production. A second essential effect of CR demonstrated by metagenomics sequencing in our recent publication is a ~1000-fold enrichment of the commensal Bifidobacteria that produce the short-chain fatty acid acetate. Ex vivo data indicates that the combination of IFN and acetate is essential to enhance the ability of myeloid cells from mice on CR to kill pathogens. Further, our RNA-seq identified that myeloid cells upregulate multiple genes related to pathogen killing in vivo during CR. This proposal builds on our recent publication and extensive preliminary data and will test the central hypothesis that CR induces memory CD8+ T cell metabolic rewiring to enhance the production of IFN, which combines with Bifidobacteria-derived acetate to increase the capacity of myeloid cells to kill pathogens. Based on our new data, this proposal will determine if (i) CR-induced metabolic reprogramming is essential to enhance memory T cell IFN production, and (ii) how the combination of memory T cell-derived IFN and microbiota-derived acetate enhances myeloid cells in this context. Altogether, we will define how CR enhances and promotes cooperation between distinct immune cells for increased pathogen control. This will be essential to achieving our long-term goal of reducing the burden of infectious disease by optimizing immunological memory.
