Neisseria meningitidis (meningococcus) is a human-restricted bacterium that colonizes the nasopharyngeal epithelium, often asymptomatically. However, occasionally, meningococci can breach the epithelial barrier, enter the bloodstream, and cause invasive meningococcal disease. Following transmission via respiratory droplets, N. meningitidis must overcome epithelial defenses and compete with the resident commensal microbiota to establish colonization. This thesis focuses on the interplay between N. meningitidis, commensal Lactobacillus spp., and epithelial host defenses during the early stages of meningococcal colonization.

A key virulence factor of N. meningitidis is the type IV pilus, which facilitates bacterial adhesion to epithelial cells and the formation of multicellular structures known as microcolonies. These microcolonies provide protection to the bacteria against host responses. By contrast, commensal bacteria such as Lactobacillus spp. can interfere with meningococcal colonization by a multitude of antipathogenic mechanisms, including co-aggregation. Additionally, host epithelial cells contribute to defense by releasing antimicrobial peptides.

Paper I showed that the formation of meningococcal microcolonies is density-dependent and responsive to temperature changes. Moreover, lactate-induced dispersal from microcolonies required both functional protein synthesis and the ability to retract pili. Paper II built on these findings by showing that the antimicrobial peptide human beta-defensin 2 (hBD2) preferentially killed single cells of N. meningitidis over those in aggregates. This bactericidal effect was both time- and dose-dependent. Interestingly, extracellular DNA could bind to hBD2, reducing its effectiveness and offering a protective mechanism for N. meningitidis. Paper III explored a host-mediated defence mechanism involving Lactobacillus crispatus, which promoted the internalization of N. meningitidis into epithelial cells. This internalization hindered bacterial transcytosis and increased the acidic vacuoles, ultimately leading to intracellular killing of the pathogen. Thus, L. crispatus supports the host in clearing the infection. Paper IV further examined the interaction between L. crispatus and N. meningitidis, identifying a co-aggregative phenotype in which L. crispatus binds to meningococcal pili. This interaction impedes proper microcolony formation, rendering the pathogen more susceptible to antimicrobial agents.