Virulence Factors of Meningitis-Causing Bacteria: Enabling Brain Entry across the Blood–Brain Barrier

Abstract

Infections of the central nervous system (CNS) are still a major cause of morbidity and mortality worldwide. Traversal of the barriers protecting the brain by pathogens is a prerequisite for the development of meningitis. Bacteria have developed a variety of different strategies to cross these barriers and reach the CNS. To this end, they use a variety of different virulence factors that enable them to attach to and traverse these barriers. These virulence factors mediate adhesion to and invasion into host cells, intracellular survival, induction of host cell signaling and inflammatory response, and affect barrier function. While some of these mechanisms differ, others are shared by multiple pathogens. Further understanding of these processes, with special emphasis on the difference between the blood–brain barrier and the blood–cerebrospinal fluid barrier, as well as virulence factors used by the pathogens, is still needed.

Potential Roles and Functions of Listerial Virulence Factors during Brain Entry

“…Neuro-invasive strains of E. coli (Ec) and Group B Streptococcus (GBS) are prevalent in cases of neonatal bacterial meningitis; Haemophilus influenzae (Hi), Neisseria meningitidis (Nm) and Streptococcus pneumoniae (Sp) are associated with bacterial meningitis in children and adults; and Lm-induced meningitis is found mainly in neonates, elderly and otherwise immunocompromised people [105]. Although the entry points of these bacteria into the body vary (respiratory tract for Hi, Nm and Sp and gastrointestinal tract for Ec, GBS and Lm), they share a similar general strategy to reach the CNS, necessitated by the constrains put on them by the structure of the vascular system and the brain: 1. adhesion to a mucosal surface (respiratory or gastrointestinal); 2. crossing of the epithelial barrier into the blood; 3. persistence in the bloodstream; 4. adhesion to microvascular endothelium/CP epithelium in the brain; 5. crossing across the blood-brain barriers [105,106]. There are differences in the approach of various bacteria at all of these stages based on the specific VF utilized, but the most relevant stages for the entry into the brain are the last two: adhesion to and penetration of the brain barriers.…”

“…There are differences in the approach of various bacteria at all of these stages based on the specific VF utilized, but the most relevant stages for the entry into the brain are the last two: adhesion to and penetration of the brain barriers. The adhesion step is administered by interaction of capsule components, pili, fimbriae and adhesins on the surface of bacteria (Inl family members in case of Lm) with multiple host cell molecules (e.g., receptors and proteoglycans), with some bacteria colonizing the surface of the cell layer before the invasion (Nm) [105,106]. The invasion step itself is the more diverse of the two-most neuro-invasive bacterial species can assumingly utilize both the paracellular and the transcellular pathway, but some seem to use only one of them (paracellular for GBS and likely transcellular for Lm).…”

“…The invasion step itself is the more diverse of the two-most neuro-invasive bacterial species can assumingly utilize both the paracellular and the transcellular pathway, but some seem to use only one of them (paracellular for GBS and likely transcellular for Lm). Paracellular entry can be achieved either by "unlocking" of the tight junctions (Nm) or by disruption of the barriers through killing of the cells in the layer with toxins (Hcp1 in Ec) or cytolysins (β-hemolysin in GBS and pneumolysin in Sp) -interestingly, LLO, the signature cytolysin of Lm, does not seem to have this role [91][92][93][94]105,106]. Transcellular entry can be direct or indirect.…”

“…Transcellular entry can be direct or indirect. While the indirect entry is based on exploitation of parasitized phagocytes, the direct entry is dependent on the induced "zipper-type" endocytosis of the bacteria through interaction with the target cell mediated by binding of bacterial surface proteins to specific cellular receptors (e.g., IbeA in Ec, InlA in Lm) [105,106].…”

Microbial Virulence Factors

“…The virulence factors that the bacteria use to cross the blood-brain barrier and cause meningitis is reviewed by Herold et al [15]. Meningitis remains a worldwide problem often associated with fatalities and severe sequelae.…”