Neisseria meningitidis is a strictly human-tropic pilus-bearing bacterium that resides in the nasopharynx as a commensal. The bacterium can sometimes reach the bloodstream, colonize the vascular wall, and trigger meningitis or, in extreme cases, purpura fulminans.
The authors had previously identified molecular and cellular mechanisms used by the bacterium to stabilize itself on the surface of endothelial cells, despite the hemodynamic constraints produced by blood flow. Thus, meningococcus uses its type IV pili (T4P) to bind to the transmembrane receptor CD147 and adhere to endothelial cells. After binding to CD147, these retractile filamentous bacterial organelles interact with the glycan chains at the N-terminal end of the β2-adrenergic receptor and mechanically activate a specific signaling pathway in the infected endothelial cells. The resulting biochemical effects rapidly anchor the bacterium to the host cell plasma membrane, stabilize it against blood flow through the formation of plasma membrane protrusions, and ultimately allow it to cross the endothelium to infect underlying tissues.
These membrane protrusions, which surround nascent colonies, are enriched in cytoskeletal proteins such as ezrin and actin.
However, the early cellular processes preceding the binding and activation of meningococcal-specific receptors remained unexplained. In particular, it was unclear how very small numbers of circulating bacteria manage to activate receptors expressed at low abundance on the host cell membrane.
The early mechanisms of bacterial interaction with its receptors were explored, starting with the study of the recruitment and dynamics of tetraspanins, proteins with a particular affinity for curved plasma membrane structures.
Meningococcus induces the early formation of tubular plasma membrane structures (TMS) in endothelial cells through a physical mechanism.
The tetraspanin CD9 accumulates in these TMS, unlike ezrin, a signaling marker, indicating that this recruitment is independent of known cellular signaling pathways. Using FRAP (fluorescence recovery after photobleaching), the authors showed that meningococcus induces the accumulation and sequestration of many transmembrane proteins in TMS, regardless of their biological function, while other transmembrane proteins are excluded.
TMS formation does not require any cellular biochemical activity: it is observable in cells fixed with paraformaldehyde, ATP-depleted cells, or isolated membrane preparations (PM sheets). TMS formation is a purely physical phenomenon that is even counteracted by actin polymerization, a consequence of cellular signaling activated by meningococcal receptors. TMS formation can be reproduced in cells incompetent for meningococcal infection, in gain-of-function experiments reconstituting the possibility of activation by the bacterium.
In conclusion, our results indicate that the initiation of TMS formation is independent of bacterium-induced signaling and depends solely on a physical phenomenon occurring at the host cell plasma membrane.
This phenomenon, known as "wetting," explains how the host cell plasma membrane, behaving like a fluid, rises along the bacterial pili due to favorable energetic constraints. Through wetting, the local concentration of meningococcal receptors is increased, making ligand-receptor interaction more likely.
Our results suggest that Neisseria meningitidis has evolved an original strategy to optimize the interaction between its pili—containing bacterial ligands—and host cell receptors exposed on the endothelial surface. By exploiting wetting, the bacterium induces a local concentration of receptors in TMS, significantly increasing the probability of ligand-receptor encounter. This mechanism is purely physical and independent of cellular signaling. We propose a novel paradigm: the probability of ligand-receptor encounter is not solely based on cellular biochemical processes but can also emerge from physical constraints, potentially providing a major evolutionary advantage to pathogens possessing type IV pili.
The concentration of receptors via wetting could be used by other bacteria and even by certain cell populations producing nanotubes.
Reference
Laurent-Granger A, Sollier K, Saubamea B, Mignon V, Goudin N, Wormser Y, Wuckelt M, Rifai M, Heng T, L'hermitte L, Conflitti M, Meyer J, Lecuyer H, Jamet A, Borghi N, Girard P, Bille E, Lavieu G, Rubinstein E, Marullo S, Coureuil M. Meningococci drive host membrane tubulation to recruit their signaling receptors. Nat Commun. 2025 Nov 25;16(1):10433. doi: 10.1038/s41467-025-65436-1. PMID: 41290585.
Financement : ANR-19-CE14-0045-002
