Sepsis is a biphasic disease characterised by acute inflammation, leading to extensive immune suppression, exposing patients to secondary infections. Many clinical trials sought to modulate sepsis induced inflammation, but this had no effect on patient mortality, primarily due to secondary infections. Recently, focus has shifted to addressing the immunosuppressive phase of sepsis, aiming to return the host’s immune system to a functional state, to prevent further deterioration from secondary infections. Previous work by Nedeva et al., (2020) identified TREML4, a triggering receptor expressed on myeloid cells (TREM) receptor, as the key regulator of immune cell death and inflammation, following polymicrobial sepsis. Genetic ablation of TREML4 in mice using CRISPR demonstrated its role in regulating many cellular responses, such as apoptosis of innate immune cells which was reduced in the absence of TREML4, leading to a higher rate of survival in the acute and chronic phase of sepsis during secondary infection with Pseudomonas aeruginosa and most recently against Candida albicans. This improved survival is due, in part, to long lasting epigenetic changes in innate immune progenitor cells of TREML4 ablated mice. Overall, epigenetic changes to progenitor cells during the early stages of polymicrobial sepsis results in an innate immune memory that protects TREML4 ablated mice from secondary infections during the chronic phase of sepsis.