Translational research in Neonatal intensive care units about Staphylococcus Capitis: from molecular characterization to clinical implications in practice – NeoSCap

Preterm birth represents the leading cause of death in children under 5 year-old throughout the world and is responsible for numerous complications. Among these complications, nosocomial late-onset sepsis (LOS, defined as sepsis occurring after 3 days of life) is highly frequent in neonatal intensive care units (NICUs). The clone NRCS-A belonging to Staphylococcus capitis species has recently emerged as a major multidrug-resistant pathogen involved in these nosocomial LOS in neonates. Previous studies about NRCS-A have revealed its specific presence in NICU settings and its worldwide dissemination. Moreover, its implication in LOS has been reported as an independent risk factor for severe morbidity, in comparison with other bacteria. Finally, several data support the hypothesis of an intestinal carriage of NRCS-A in neonates, suggesting that translocation from the gut to the blood could be involved in the pathogenesis of this clone. The present NeoSCap project aims to provide a better understanding of this pathogen, from the mechanisms of diffusion and persistence in NICUs to the mechanisms involved in LOS in preterm neonates and its individual impact at the patient level.

First, NeoScap project aims to investigate the determinants of the high affinity of NRCS-A to NICUs and preterm neonates using an original transcriptomic approach in the “real-life” conditions of NICU environment. The confirmation and exploration of the role of these genes of interest will be based on targeted inhibition (gene knockdown) using the recent well-described CRISPR-cas9 method, then the mutant strains will be compared to the wild type counterpart for different phenotypic features.
Second, because several studies have suggested that the reservoir of NRCS-A is likely the gut rather than the skin, the mechanisms and steps of NRCS-A gut colonization then translocation and infection will be deciphered. An original approach combining in vitro, ex vivo and in vivo models is proposed to address this hypothesis. These models will take into account almost all the factors likely involved in the NRCS-A colonization and translocation process, i.e. the immaturity of the newborn’s gut, the specificity of microbiota composition in the neonatal period, the possible effect of local inflammation, the impact of previous vancomycin administration and the influence of hormonal impregnation in the neonates.
Third, a major clinical issue will be addressed concerning eradication of NRCS-A from NICU environment. NeoSCap project will investigate the steps of NRCS-A environmental persistence (resistance to antiseptics, biofilm production) in order to define new strategies for eradication. Then different methods (including combination of antiseptic molecules but also the innovative use of a steam cleaning) will be tested directly on running incubators mimicking “real-life” use. The results of this investigation may directly impact the daily practices in NICU settings by the way of proposing new protocols or approaches of disinfection.
Finally, we will strengthen clinical data about S. capitis colonization and infection, by exploring risk factors and long-term outcome of colonized preterm neonates. The access to the nationwide database of the prospective French cohort Epipage 2 is a great opportunity to provide valuable data on this important question.

To conclude, the originality of our project is its translational approach with links between scientific aspects (genomic, transcriptomic, pathophysiological explorations) and clinical purposes (disinfection practices, patient outcome). Our proposal fully addresses the global issue and the major impact of the multidrug-resistant NRCS-A clone in preterm infants, which affects almost all the NICU settings in France but also in numerous countries throughout the world. This topic is in line with a priority scientific axis of the 2019 ANR plan that concerns “Antimicrobial resistance”, a public health issue at the global scale.