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BCG-induced nonspecific protection from neonatal sepsis

University of British Columbia

Bacterial sepsis remains the leading cause of infectious deaths in newborns. Our understanding of the neonatal immune system, and what controls the decision between survival and death remains rudimentary, despite decades of effort. Bacille-Calmette–Guérin (BCG) vaccination, a century-old tuberculosis prevention, also reduced neonatal all-cause mortality by 40% within 3 days of administration in clinical studies. This protection was termed BCG’s nonspecific effects (NSE), or heterologous immunity. The scale and speed of this beneficial NSE was deemed biologically improbable, and potentially due to artifacts of trial design. It was also argued that proof-of-mechanism was required to have confidence in BCG NSE, which I specifically address in my thesis. A neonatal murine sepsis model was modified for increased standardization and reproducible study of both the neonatal response to sepsis and the exploration of BCG’s NSE mechanism. I hypothesized that survival from bacterial sepsis could be mediated through either an antimicrobial or anti-inflammatory response, or through both. I observed neonatal weight change, and designed novel health scoring for righting reflex and mobility that was used to accurately predict survival through mathematical modelling. Predicted survival significantly associated with lower systemic bacterial burdens, implicating neonatal antimicrobial responses with improved survival. This was further supported by differing disease kinetics between bacterial- and endotoxin-induced sepsis. As in human newborns, BCG vaccination of neonatal mice reduced the risk of death from bacterial sepsis by 40% within 3 days of vaccination. Neonatal and juvenile mice had increased survival and lower bacterial burden with BCG vaccination, while a delay of challenge by one week, or adult vaccination, was not protective. This indicated fast-acting but transient and age-dependent antimicrobial protection. I identified that BCG-induced mature neutrophil expansion was necessary and sufficient for protection. The molecular mechanism of rapid neutrophil expansion involved emergency granulopoiesis, with sequential G-CSF cytokine production, CEBP-β gene transcription, granulocyte macrophage progenitor cell expansion, immature neutrophil expansion, and mature neutrophil expansion. BCG’s ability to reduce neonatal bacteria-induced septic death by 40% in a rigorously controlled experimental setup, plus the insight into underlying mechanistic events, provide direct evidence to support BCG’s NSE and the ability to reduce neonatal mortality.

Text

2020-08-25

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75679

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/