Pathogenic Triad in Bacterial Meningitis: Pathogen Invasion, NF-κB Activation, and Leukocyte Transmigration that Occur at the Blood-Brain Barrier

Abstract

Bacterial meningitis remains the leading cause of disabilities worldwide. This life-threatening disease has a high mortality rate despite the availability of antibiotics and improved critical care. The interactions between bacterial surface components and host defense systems that initiate bacterial meningitis have been studied in molecular and cellular detail over the past several decades. Bacterial meningitis commonly exhibits triad hallmark features (THFs): pathogen penetration, nuclear factor-kappaB (NF-κB) activation in coordination with type 1 interferon (IFN) signaling and leukocyte transmigration that occur at the blood-brain barrier (BBB), which consists mainly of brain microvascular endothelial cells (BMEC). This review outlines the progression of these early inter-correlated events contributing to the central nervous system (CNS) inflammation and injury during the pathogenesis of bacterial meningitis. A better understanding of these issues is not only imperative to elucidating the pathogenic mechanism of bacterial meningitis, but may also provide the in-depth insight into the development of novel therapeutic interventions against this disease.

Keywords: NF-κB activation; bacterial meningitis; blood-brain barrier; leukocyte transmigration; pathogen invasion; pathogenic triad.

Figure 1

Flow chart of the pathogenic triad in bacterial meningitis (BM). (A) Bacterial pathogens adhere to brain microvascular endothelial cells (BMEC) that is the major component of the blood-brain barrier (BBB) and may then transcytotically pass to subendothelial tissues. (B) The nuclear factor-kappaB (NF-κB) is activated by bacterial virulence factors (BV) through their binding to BMEC membrane (CM) receptors (BVR), which can activate the enzyme IκB kinase (IKK) complex (α/β/γ). IKK, in turn, phosphorylates the NF-κB inhibitor IκBα, which results in dissociation of IκBα from NF-κB and eventual degradation of IκBα by the proteosome. The activated NF-κB is then translocated into the nucleus where it cooperatively activates gene transcription with other proteins such as coactivators and RNA polymerases. (C) The sequential steps are shown with numbers. (1), Leukocyte free in circulation and non-adhesive to endothelial cells; (2), Leukocyte tethered to endothelium and rolling under force of blood flow; (3), Leukocyte bound to endothelium and migrating via integrins and intercellular adhesion molecule-1 (ICAM-1); (4), Extravasation of leukocyte from blood vessel with the involvement of junctional adhesion molecule (JAM) and platelet endothelial cell adhesion molecule-1 (PECAM-1); and (5), Leukocyte migrates to source of infection or injury through integrins.

Figure 2

Bacterial adhesion to and invasion of human BMEC (HBMEC). Transmission Electron Microscopy shows meningitic E. coli K1 (E44) adhesion to (A) and invasion across (B) human BMEC. E. coli closely contacted the human BMEC membrane and elicited its own uptake at the site of infection (A). Intracellular bacteria are identified in membrane-bound vacuoles after 30 min of incubation (B). Arrows indicate the processes of bacterial adhesion (A) and subsequent invasion (B).

Figure 3

Regulation of NF-κB and type 1 IFN signaling pathways by bacterial effectors. Bacterial infection triggers receptor-dependent activation of the signaling pathways at the host cell membrane. Receptor activation triggers signaling protein phosphorylation, which in turn activates the nuclear factor-kappaB (NF-κB) pathways via activation of the IκB kinase (IKK) complex and up-regulate interferon-regulatory factor (IRF) family of transcription factors through MyD88-mediated signaling. E. coli K1 IbeA-binding proteins Vimentin and PTB-associated splicing factor (PSF) act in concert to activate NF-κB. NF-κB activation induced by S. pneumoniae depends on the host factors toll-like receptors 2 (TLR2) and 4 (TLR4), and their ligands lipoteichoic acid (LTA) and lipopolysaccharide transport (LPT) (pneumococcal cell wall compounds). The NF-κB activation induced by L. monocytogenes depends on the Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) and internalin B (InlB) receptor. The two coordinated signaling pathways result in production of inflammatory factors (NF-κB) and IFN-β (type 1 IFN signaling).

Figure 4

Transendothelial migration of polymorphonuclear neutrophil (PMN) across BMEC in response to meningitic infections caused by bacterial pathogens. PMN adhesion and crawling from the vascular lumen are the firstly two steps to close to the endothelial cells, and then PMN transmigration across the BBB through both the paracellular and transcellular pathways.

Figure 5

Mechanistic triad of bacterial meningitis (BM): Pathogen penetration, NF-kB activation and leukocyte transmigration that occur at the BBB. BM caused by pathogens usually begins with local tissue adhesion and colonization of the potentially meningitic microorganisms. After successful traversal of the local tissue barrier (e.g., the gut barrier for enteric pathogens), a high degree of bacteremia is required for penetration of pathogens across the BBB to cause meningitis. NF-kB activation, a mechanistic link, contributes to both pathogen penetration and leukocyte transmigration across the BBB. The NF-kB signaling pathway can serve as a drug-discovery platform.