The Host-Pathogen Interactions and Epicellular Lifestyle of Neisseria meningitidis

Abstract

Neisseria meningitidis is a gram-negative diplococcus and a transient commensal of the human nasopharynx. It shares and competes for this niche with a number of other Neisseria species including N. lactamica, N. cinerea and N. mucosa. Unlike these other members of the genus, N. meningitidis may become invasive, crossing the epithelium of the nasopharynx and entering the bloodstream, where it rapidly proliferates causing a syndrome known as Invasive Meningococcal Disease (IMD). IMD progresses rapidly to cause septic shock and meningitis and is often fatal despite aggressive antibiotic therapy. While many of the ways in which meningococci survive in the host environment have been well studied, recent insights into the interactions between N. meningitidis and the epithelial, serum, and endothelial environments have expanded our understanding of how IMD develops. This review seeks to incorporate recent work into the established model of pathogenesis. In particular, we focus on the competition that N. meningitidis faces in the nasopharynx from other Neisseria species, and how the genetic diversity of the meningococcus contributes to the wide range of inflammatory and pathogenic potentials observed among different lineages.

Keywords: evolution; inflammation; invasive meningococcal disease; microbiome; pathogenesis.

Figure 1

Presence of known genes associated with pathogenesis among meningococcal lineages. The presence of genes associated with pathogenesis mentioned in this review are marked as either present (gene is present in >80% of isolates from the lineage), variably present (gene is present in 20-80% of the isolates from the lineage), or absent (gene is present in <20% of isolates from the lineage). For references see text. Lineages here are defined according to the framework of Mullally et al., 2021. Where specific variants of a virulence gene/island are known, i.e. for capsular serogroup, class of pilE, pglB allele, and IgA protease cleavage type, the variant predominantly associated with each lineage is indicated. The phase-variation status and known regulators of each gene are also indicated. The known regulators of each gene and the presence of phase-variation and hypervariability are also indicated. * = genes encoding DNA repair enzymes with a known role in resistance to oxidative and nitrostative stress including: nexo, nape, nth, mutM, and dinG.

Figure 2

Interactions of N. meningitidis at the nasopharyngeal surface. (A) Following acquisition, Nme must survive against host defences, interactions with other members of the microbiome, and intra-specific competition in order to inhabit the mucus of the nasopharynx. Eventual binding of the epithelial surface results in intimate association and passage into the submucosa by transcytosis. (B) Binding of epithelial cells occurs by interaction of Neisserial surface structures with their cognate receptors, resulting in inflammation, cellular restructuring, and transcytosis. This figure was created using Biorender.com.

Figure 3

Interactions of N. meningitidis in the systemic circulation. (A) In the bloodstream, Nme must resist antibody- and complement-mediated killing, acquire iron, and attach to the capillary endothelial surface to form microcolonies. Once attached, Nme possesses several mechanisms to resist the actions of phagocytic cells, including neutrophils and macrophages. (B) Binding of endothelial cells occurs by interaction of meningococcal surface structures with their cognate receptors, resulting in cortical plaque formation, transcytosis, and breakdown of tight junctions. This figure was created using Biorender.com.