Innate immune training in the neonatal response to sepsis

Area of Science:

• Immunology
• Neonatal Research
• Vaccinology

Background:

• Neonates, particularly premature infants, face high mortality risks from infections.
• Live attenuated vaccines, like BCG, are known to confer non-specific effects (NSEs) against secondary infections in newborns.
• Trained immunity and emergency granulopoiesis are implicated in these beneficial NSEs, but their impact on myeloid subsets remains unclear.

Purpose of the Study:

• To investigate how Bacillus-Calmette-Guérin (BCG) vaccination reprograms myelopoiesis in neonates.
• To determine the influence of BCG-induced trained immunity on the host's response to polymicrobial sepsis.
• To elucidate the specific myeloid subsets and transcriptional changes affected by early-life BCG vaccination.

Main Methods:

• BCG vaccination in neonatal models.
• Flow cytometry to analyze myeloid progenitor populations (LSK, GMP) and CD11b+Gr1+ cells.
• Assessment of oxidative metabolism and T-cell stimulatory capacity of myeloid cells.
• Single-cell RNA sequencing of neonatal splenocytes.

Main Results:

• BCG vaccination improved survival rates during polymicrobial sepsis.
• BCG expanded key myeloid progenitor subsets (LSK, GMP) and increased CD11b+Gr1+ cells.
• Vaccination enhanced myeloid cell oxidative metabolism and T-cell proliferation capacity.
• Single-cell RNA sequencing revealed broad transcriptional reprogramming of myeloid subsets, promoting neutrophil/monocyte maturation, antimicrobial activity, and suppressing inflammation and myeloid-derived suppressor cells.

Conclusions:

• Early-life BCG vaccination fundamentally reorganizes the neonatal myeloid landscape.
• This reprogramming enhances the host's protective response to subsequent polymicrobial infections.
• BCG-induced trained immunity provides significant benefits against sepsis by modulating myelopoiesis.