Taurine and a-ketoglutarate induce innate immune memory in macrophages and facilitate the reactivation of latently infected HIV by β-glucan and MDP 9276

Abstract Description The induction of innate immune memory and consequent trained immunity has several potential applications within the biomedical field. For instance, training with established stimuli such as BCG vaccination and β-glucan has previously shown to reduce microbial infections and cancer growth; although, some cases presented side effects, such as autoimmune disease. By identifying new trained immunity stimuli with less side effects, this approach could have broad applications, such as the reactivation and killing of latent HIV. Using a high throughput screening assay, we found that the metabolites taurine and α-ketoglutarate (AKG) both induced innate immune memory in macrophages. Our studies further showed that taurine and AKG enhanced the training effect of previously identified stimuli such as Syk kinase inhibitors (SYKi IV or R406), β-glucan, and Muramyl dipeptide (MDP), the active component of the BCG vaccine. Chromatin immunoprecipitation analysis of taurine and AKG treated macrophages showed enrichment of H3K4Me3, a transcriptional activation and innate immune memory marker, at the TNF and IL6 promoters. Our studies also showed that combined application of AKG or taurine with either MDP, β-glucan or SYKi IV, can reverse HIV latency in cell line models more efficiently than training with MDP, β-glucan or SYKi IV alone. We also show that combined application of taurine or AKG with MDP, β-glucan, or SYKi IV can efficiently reactivate HIV from PBMCs of people living with HIV. Funding Sources This work was supported by the Intramural Research Program of NIAID, NIH and the Office of the AIDS Research at NIH. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)