The Role of Gasdermin D in Escherichia Coli K1 Bacterial Brain Infections

Abstract

Escherichia coli K1 is a leading cause of gram-negative bacterial meningitis in neonates. While previous research has revealed mechanisms by which E coli K1 translocates from the periphery to the brain, little is known about the steps of pathogenesis and innate immune response once the pathogen has reached the cerebral spinal fluid, meninges, and central nervous system (CNS). In 2015, a novel molecule termed gasdermin-D (GSDMD) was described to drive cell death in the context of bacterial lipopolysaccharide (LPS) mediated sepsis. GSDMD is activated by caspase cleavage, which induces proinflammatory cytokine release by forming pores at the cell plasma membrane, leading to pyroptosis. However, the role of GSDMD in meningitis in the brain has not been investigated. Given that GSDMD has previously been described to drive detrimental proinflammatory cell death in LPS sepsis models, we hypothesize that GSDMD activation may play an important role in the context of E. Coli K1 pathogenesis of the CNS and CNS associated tissues such as the meninges. Herein, our in vitro data shows that, GSDMD is important for E. coli K1 induced cell death of microglia, which are the CNS resident innate immune cells. Moreover, by intracisternal delivery of E. coli K1 to the mouse CSF and brain, we observed that Gsdmd -/- mice were more susceptible to death and had higher meningeal immune infiltration compared to wild-type (WT) mice after infection. In the future, we plan to characterize how bacterial spreading and invasion of the CNS differs between Gsdmd-/- and WT mice, and further characterize the neuronal and immune response differences in these mice after infection. This study will provide insights into the role of GSDMD in host defense against E. coli once it invades the CNS.