Molecular Mechanisms Involved in Escherichia coli K1 and Haemophilus influenzae Type a Blood-Brain Barrier Impairment

Abstract

Blood Brain Barrier (BBB) is a protective barrier against possible neurotoxic molecules, such as proteins or endogenous metabolites, xenobiotics derived from the environment or ingested with the food. At the same time, BBB selectively allows the cross of ions and nutrients from blood into the CNS by active transport. BBB is made of brain microvascular endothelial cells, characterized by the presence of tight inter-endothelial junctions and the lack of fenestrations, and pericytes, the cells closest to brain endothelial cells with which they share a common basement membrane. Bacterial meningitis is a common and severe Central Nervous System (CNS) infection, caused by different pathogens, including Escherichia coli K1 (E. coli K1) and Haemophilus influenzae type a (Hia). During E. coli K1 meningitis, CNS cells release pro-inflammatory mediators, while the bacterium promotes the association between Vascular Endothelial Growth Factor Receptor 1 (VEGFR-1) and p85 subunit of PI3K. All these events lead to increase of BBB permeability and bacterial invasion of microvascular endothelial cells. It is still unknown if the emergency of invasive Hia disease is due to the serotype replacement after the wide use of Hib vaccine for child immunization. Despite Hia is now recognized as a pathogen responsible of disease comparable to Hib, no in vitro studies are conducted to clarify the mechanisms by which Hia is able to cross BBB, leading to meningitis. Aim of the study was to understand the molecular mechanisms through which E. coli K1 (first study) and Hia (second study) are able to cross BBB and to cause meningitis. Results of first showed that, after E. coli K1 infection, endothelial cells secrete VEGF, which target VEGFR-1 on the membrane of adjacent pericytes and determine their leak, leading to increased BBB permeability and allowing bacterial invasion. The second study demonstrated the correlation between the adenosine signaling pathway and BBB breakdown, highlighting the modulatory role of A2A and A2B adenosine receptors. In conclusion, association of an antibiotic therapy with a drug able to block the VEGFR-1 on pericytes could represent a novel strategy against E. coli K1 meningitis, while further studies on involvement of pericital adenosine receptors activation in Hia infection could be promising for the development of new pharmaceutical targets.