Brittany Seman, February 22
Neonates are highly vulnerable to bacterial infections and are at an increased risk of mortality in the first days of life due to a unique immune profile. Globally, nearly 3 million neonates are infected by bacterial pathogens, with high mortality rates in these susceptible individuals. The bacterial pathogen Escherichia coli (E. coli), serotype O1:K1:H7, is a leading cause of neonatal sepsis, and is responsible for significant mortality. Given the present severity of these infections, even with current antimicrobial treatments, our laboratory has established multiple infection models to study the host-pathogen interactions that occur during the neonatal period of life. We have developed a neonatal mouse sepsis model to understand how the immunoregulatory cytokine, interleukin-27 (IL-27), affects the host immune response to bacterial sepsis. We have found that absence of IL-27 signaling promotes survival and increased infection outcome in neonatal mice compared to mice that have IL-27 expression. This study suggests that neutralization of IL-27 could become a novel immunotherapeutic to improve overall infection outcome in neonates. We have also developed a human in vitro infection model, using umbilical cord blood, to study the importance of low-density granulocytes (LDGs) during host-pathogen interactions with E. coli. We have found that LDGs impair the ability of other phagocytes to clear bacteria efficiently by releasing extracellular DNA (eDNA) during co-culture. This reduction in bacterial clearance by phagocytes in the presence of LDG eDNA may compromise protective immunity during infection. Thus, LDG eDNA could become a therapeutic target to improve overall bacterial clearance and potentially increase infection outcome. Overall, these studies combined aim to further enhance our understanding of neonatal sepsis in the context of host immune response, and create a strong initiative to develop immunotherapies that can combat these severe infections and improve survival outcomes in neonates.