Importance of 2 hydroxymyristate on lipid A structure on Enterobacter neonatal sepsis pathogenesis – ENDOSEPSIS

Enterobacter is a known pathogen of fulminant sepsis in neonates as well as in immunosuppressed patients. We have recently shown that a structural modification of lipid A in Enterobacter endotoxins, specifically the presence of 2-hydroxymyristate (2-HM), is associated with excess neonatal mortality during Enterobacter septic shock. The working hypothesis of this research proposal is that 1) 2-HM interferes with the host response 2) in a manner specific to certain immunological and/or developmental characteristics of the host. In order to confirm this hypothesis, two cohorts have been set up and will be studied: the first one (SENSE- French multicentre cohort) gathers clinical characteristics as well as 88 Enterobacter strains responsible for bacteremia in neonates. The second (SEPSIS-cohort) was set up in Benin by a consortium including the CNRS, IRD and bioMérieux and includes clinical, immunological and microbiological monitoring of 580 infants, 180 of whom developed neonatal sepsis. Our project will use Enterobacter as a model and will be extended to two other pathogens possessing 2-HM, namely Klebisella pneumoniae and Serratia marcencens. Our project will be structured around three workpackages: WP1. Genotypic and phenotypic characterisation of enterobacteria strains isolated from bacteremia, and characterisation of the host transcriptomic response; WP 2. Role of lipid A structural modifications on the host response; and WP 3. Functional validation of candidate genes. This project should provide new insights into the functional role of structural modifications of endotoxins and their role in the pathophysiology of Gram-negative sepsis.