Project Details
Projekt
Signal transduction during central nervous system invasion by Listeria monocytogenes - the role of host cell factors with a focus on CD44.
Subject Area
Molecular and Cellular Neurology and Neuropathology
Pediatric and Adolescent Medicine
Pediatric and Adolescent Medicine
Term
from 2017 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 349107993
Infections of the central nervous system (CNS) can lead to meningitis, a life-threatening disease in humans, which provokes severe illness and death worldwide. The Gram-positive bacterium Listeria monocytogenes (L. monocytogenes) is an important pathogen causing meningitis in newborn as well as in elderly and immunocompromised people. During the course of disease the bacteria have to enter the CNS by crossing either the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCSFB). Of major importance during these processes are interactions between bacterial virulence factors and host cell receptors. Invasion of L. monocytogenes into host cells involves action of the listerial surface proteins InlA and InlB, which bind to E-cadherin and the receptor Met, respectively. Interestingly, the co-receptor CD44v6 has been described to be involved during listerial invasion mediated by interaction of InlB with Met. The interactions between virulence factors and their receptors lead to the activation of diverse host cell signal transductions pathways required for bacterial entry. Although progress has been made in understanding how L. monocytogenes enters the CNS, the exact mechanisms are still poorly understood. E.g. only limited efforts have been made to elucidate the roles of InlA and InlB during invasion of the CNS. This project now aims at deciphering the mechanisms of listerial brain entry at the BBB and the BCSFB. For this purpose an in vitro model of the BCSFB based on an epithelial cell line obtained from a choroid plexus papilloma will be employed; human brain microvascular endothelial cells will substitute as in vitro model of the BBB. Using these model systems we will characterize the roles of listerial virulence factors, their host cell target proteins, and the signalling pathways involved during entry of L. monocytogenes into host cells. Here, the functions of the co-receptor CD44 and its variant CD44v6 are of major interest. To decipher the role of CD44/CD44v6 in vivo, wild-type and knock-out mice will be infected with L. monocytogenes. Blocking peptides against CD44v6 and mice with specific knock-out of CD44/CD44v6 in the BBB and the BCSFB will be used to determine the roles of CD44/CD44v6 during disease and CNS invasion by L. monocytogenes.
DFG Programme
Research Grants
