Investigating age- and virulence factor- dependent innate immune activation during neonatal meningitis associated E. coli infection
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Neonatal meningitis-associated Escherichia coli (NMEC) is a leading cause of early-onset sepsis and meningitis. While current antibiotic protocols have significantly reduced mortality associated with neonatal sepsis and meningitis, surviving infants are at a significantly increased risk of developing life-long neurologic impairment compared to healthy infants. This continued risk of lasting neurologic damage along with a recent rise in antibiotic resistant NMEC strains has precipitated a need for new therapeutic strategies. Targeted immune-based therapeutics may serve as desirable adjunct therapies; however, there are many challenges to their development. The neonatal immune system is immature compared to the immune system of adults, leading to an increased risk of infection. Here we assess the role of IL-1 secretion, which is known to be diminished in neonates, in the pathogenesis of a murine model of NMEC infection. We further highlight one potential mechanism for decreased IL-1 secretion during the neonatal period. To further complicate the development of immune-based therapeutics aimed at treating NMEC infection, NMEC strains can possess many different virulence factors with the potential to alter immune cell activation. While some of these factors, such as OmpA, have been well-characterized in the context of NMEC infection, many potential virulence factors have not. Here we show that the pore-forming toxin [alpha]-hemolysin activates purinergic receptors, leading to improved bacterial clearance and decreased mortality in a neonatal mouse model of NMEC infection. Together, the data presented here provides new insight into both neonatal immunity and the role of virulence factor-specific immune activation on the pathogenesis of NMEC infection, and may serve as a stepping stone for the development of not only new immune-based therapeutics, but also new diagnostic and prognostic tools for use during neonatal infection.
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Ph. D.