Interaction mechanisms of encapsulated meningococci with eucaryotic cells: what does this tell us about the crossing of the blood–brain barrier by Neisseria meningitidis?

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Abstract

An important feature of Neisseria meningitidis is its ability to invade the meninges. This requires that bacteria cross the blood–brain barrier (BBB), which is one of the tightest barriers of the body. N. meningitidis has, therefore, evolved very sophisticated means by which it circumvents the physical properties of this cellular barrier. Recent advances have allowed the identification of several steps that might occur in the interaction of N. meningitidis with the BBB and the transit of the bacteria to the meninges.

Introduction

Neisseria meningitidis (the meningococcus) is an extracellular pathogen responsible for meningitis and septicaemia. The meningococci colonise the nasopharynx and spread from person to person by droplet infection. In a small percentage of colonised people, the meningococci gain entry into the bloodstream, where it causes meningococcemia and/or progresses to the cerebrospinal fluid (CSF) to cause meningitis after crossing the blood–brain barrier (BBB). In order to reach the meninges from the throat, N. meningitidis has to interact with two cellular barriers: firstly, one in the nasopharynx to invade the bloodstream, and secondly, the BBB in the brain. The BBB is made of two different structures. One structure consists of the endothelium of the brain capillaries, which differ from the endothelial cells present in peripheral capillaries by the presence of tight junctions limiting the paracellular flux [1]. The second structure responsible for the BBB is the choroidal plexus, which is the major site of CSF synthesis and is located in the ventricles [2]. In the choroidal plexus, the endothelial cells are fenestrated and the BBB is formed by tight junctions at the ventricular surface of the epithelial cells.

To be able to invade the meninges after colonisation of the throat, meningococci need two kinds of virulence factors: first, attributes responsible for bloodstream survival and dissemination, and second, components mediating the meningococcal interaction with cellular membranes leading to the bloodstream invasion from the throat, and the crossing of the BBB. Among the former, the importance of the polysaccharide capsule was established by the observation that noncapsulated isolates are usually found in the nasopharynx, whereas bacteria recovered from the blood or the CSF are capsulated. Regarding the latter virulence factors, several bacterial components capable of mediating the interaction of N. meningitidis with cells have been described; however, the sequence of events that take place when meningococci interact with mammalian cells and the events that lead to the crossing of the BBB is far from completely understood. This review discusses the recent developments concerning the bacterial attributes by which virulent N. meningitidis may interact with human cells, and the mechanisms by which the meningococcal cell interactions may lead to the crossing of a cellular barrier such as the BBB.

Section snippets

Meningococcal pili, the indispensable attribute

Pili are filamentous structures emanating from the bacterial surface. They are of paramount importance to the pathogenic process, as evidenced by the fact that primary cultures of clinical isolates are always piliated. In vitro, their expression is essential in mediating the interaction between encapsulated meningococci and both epithelial and endothelial cells, because nonpiliated bacteria are unable to adhere and/or to invade these cells [3, 4]. In addition to this effect, meningococcal pili

Opa and Opc proteins

The Opa (Class 5) proteins are basic outer membrane proteins with a molecular weight of ∼28 kDa. Their migration on polyacrylamide gels is heat modifiable [37]. The Opc protein is restricted to a subset of N. meningitidis strains, whereas Opa proteins seem to be widely present in a variety of N. meningitidis strains. A comparison of sequences of Opa variants show that these proteins vary mainly at two hypervariable regions, HV1 and HV2 [13]. Opc also undergoes phase variation, and data suggest

How do these mechanisms relate to the crossing of the BBB?

Recent in vivo data have been obtained taking advantage of a case of fulminant meningococcemia where death occurred before antibiotic treatment, at the time when the bacteria were crossing the BBB [33]. At this stage meningococci were found adhering to the endothelial cells of both the choroid plexus and the meninges, thus confirming that N. meningitidis is capable of interacting with the components of the BBB, and that this interaction is likely to be required for CSF invasion. Regarding the

Conclusion — why the meningeal tropism?

The reasons for the meningeal tropism of N. meningitidis are unclear. None of the bacterial attributes identified as mediating the crossing of a cellular barrier by meningococci are specific to the BBB; they have usually been identified using other cell types other than those belonging to the BBB. Furthermore, meningococcus interacts with most human cell types, and in vivo is seen adhering to most of the endothelial cells of the body. One explanation for the meningeal tropism could be that yet

Acknowledgements

Thanks to C Tinsley for a careful reading of this manuscript. The work in the laboratory of X Nassif is supported by INSERM, Université René Descartes Paris 5, the DRET and the Fondation pour la Recherche Médicale.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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