Host cell-derived lactate functions as an effector molecule in Neisseria meningitidis microcolony dispersal

Abstract

The development of meningococcal disease, caused by the human pathogen Neisseria meningitidis, is preceded by the colonization of the epithelial layer in the nasopharynx. After initial adhesion to host cells meningococci form aggregates, through pilus-pilus interactions, termed microcolonies from which the bacteria later detach. Dispersal from microcolonies enables access to new colonization sites and facilitates the crossing of the cell barrier; however, this process is poorly understood. In this study, we used live-cell imaging to investigate the process of N. meningitidis microcolony dispersal. We show that direct contact with host cells is not required for microcolony dispersal, instead accumulation of a host-derived effector molecule induces microcolony dispersal. By using a host-cell free approach, we demonstrated that lactate, secreted from host cells, initiate rapid dispersal of microcolonies. Interestingly, metabolic utilization of lactate by the bacteria was not required for induction of dispersal, suggesting that lactate plays a role as a signaling molecule. Furthermore, Neisseria gonorrhoeae microcolony dispersal could also be induced by lactate. These findings reveal a role of host-secreted lactate in microcolony dispersal and virulence of pathogenic Neisseria.

Commensal Neisseria cinerea impairs Neisseria meningitidis microcolony development and reduces pathogen colonisation of epithelial cells

“…Interestingly, we found no evidence of N. cinerea microcolony dispersal over the course of infection (16 h), suggesting that this may be a characteristic limited to pathogenic Neisseria. The biological significance of this is unclear, but dispersal may allow pathogenic Neisseria to disseminate, invade the epithelial layer and cause disease [13,37,44,45]. Further work with other non-pathogenic Neisseria species is warranted, as defining pathogen specific properties linked to dissemination may provide insights into novel approaches for infection control.…”

“…Meningococci proliferate on cells and form microcolonies through Tfp-mediated interactions, enhancing the ability of bacteria to withstand shear forces [30]. Furthermore, on epithelial cells microcolony dispersal is induced by lactate [13] or Tfp modification [12] and may allow bacteria to adhere to new sites, disseminate to new hosts, or invade [12,13]. To determine whether N. cinerea shows similar dynamics, we analysed microcolony formation on epithelial cells using live imaging.…”

“…Adhesion to epithelial cells is key for colonisation and is mediated largely by type IV pili (Tfp) [3,4] which induce localisation of host proteins such as CD44 at the site of meningococcal attachment [5,6], while ezrin, actin and cholesterol accumulate beneath adherent bacteria [6][7][8][9]. Meningococci also induce extensions of the plasma membrane of epithelial cells [9][10][11] and form microcolonies on the surface, which fuse, expand and disperse, allowing dissemination of bacteria [12,13].…”

A virulence-associated filamentous bacteriophage of Neisseria meningitidis increases host-cell colonisation

“…meningitidis [28]. In our model of adhesion under flow conditions, the permanent renewal of the medium prevents the increase of lactates concentration and the subsequent dispersal of bacteria.…”

RNA Atlas of Human Bacterial Pathogens Uncovers Stress Dynamics Linked to Infection

“…We also included exposure to specific in vitro virulence inducing conditions, such as shifting Yersinia pseudotuberculosis from 26°C to 37°C and depleting extracellular Ca 2+ , L-lactate supplementation for Neisseria spp. (Sigurlasdottir et al, 2017), and presence of charcoal-like resin XAD-4 in the growth medium for Listeria monocytogenes (Ermolaeva et al, 2004) ( Figure 1B). For some species, such as Mycobacterium tuberculosis and Legionella pneumophila, virulence inducing conditions are unknown and were not performed.…”