Innate immune training in the neonatal response to sepsis

Neonates, especially those born prematurely, are highly vulnerable to infection-induced mortality. Numerous observational and immunological studies in newborns have shown that live attenuated vaccines have beneficial, non-specific effects (NSEs) against secondary infections to unrelated pathogens. These beneficial effects have been attributed to trained immunity, and emergency granulopoiesis plays an essential role. However, trained immunity has been shown to affect multiple myeloid subsets and how trained immunity influences the host protective response is still undefined. Here we show that Bacillus-Calmette-Guérin (BCG) vaccination improves survival to polymicrobial sepsis by simultaneously reprogramming broad aspects of myelopoiesis. Specifically, BCG vaccination expands multiple myeloid subsets, including the lineage (Lin)^-Sca- 1⁺c-kit⁺ (LSK) and granulocytic-macrophage progenitors (GMPs), and increases CD11b⁺Gr1⁺ cell number, as well as their oxidative metabolism and capacity to stimulate T-cell proliferation in response to sepsis. Single-cell RNA sequencing of neonatal splenocytes suggests that BCG-vaccination changes the broad transcriptional landscape of multiple myeloid subsets. The result is the maturation of various neutrophil and monocyte subsets, stimulation of antimicrobial processes, and suppression of inflammatory pathways and myeloid-derived suppressor cell transcription. These findings reveal that BCG administration early after birth fundamentally reorganizes the myeloid landscape to benefit the subsequent response to polymicrobial infection.