Certain pathogens make themselves at home in the human body by invading cells and living off the plentiful amenities on offer there. However, researchers at the Max Planck Institute for Infection Biology, Berlin, together with colleagues at Harvard University, have discovered a contrary strategy to ensure infection success: some pathogens can actually delay their entry into cells to ensure their survival. Upon contact with a cell, these bacteria engage signaling molecules in the cell and trigger a local strengthening of the cellular skeleton that resists pathogen entry. This strategy, unknown until now, is used by the sexually transmitted bacterium Neisseria gonorrhoeae, as well as by an important intestinal pathogen.
The findings will be published online next week in the open-access journal PloS Biology.
Infection with Neisseria gonorrhoeae, the causative agent of gonorrhea, can lead to inflammation of the urogenital tract, the uterus and ovaries. By means of thread-shaped structures on its surface called pili, the bacterium attaches to the surface of host cells where it can multiply. Only during the later stages of infection will the bacteria penetrate the cells and occasionally advance into deeper tissues to find further breeding grounds.
Until now scientists were firmly focused on understanding the tricks used by these pathogens to enter cells. Project leader Thomas F. Meyer of the Max Planck Institute of Infection Biology and the Berlin-based researchers' work, however, suggests that bacteria may take just as much trouble to resist cell entry. Host cells produce tiny vesicles at their surface that take up nutrients, etc., from the exterior; inadvertently, these vesicles also transport attached bacteria into the interior. The researchers' new work sheds light on the signals that prevent the bacteria from being 'swallowed'. Upon fastening themselves to the cell surface, the bacteria induce a sequence of events that results in strengthening of the cell skeleton directly beneath the point of attachment. The structural protein actin is recruited to attachment sites, where it forms a strong, supportive filament. Prior to this, another structural protein called caveolin-1 and the signaling proteins VAV2 and RhoA are recruited towards the cell membrane. Together, these proteins effectively maintain N. gonorrhoeae in the extracellular milieu.
These results provide a new perspective on the course of infections: "For a long time it was thought that most pathogens strive to enter cells quickly; however, the opposite may be the case," comments Meyer "It seems the bacteria prolong their extracellular existence in order to survive." By anchoring to the cell with their pili and assembling an underlying support skeleton, the bacteria may be buffered against the often inhospitable conditions of the extracellular environment.
By extending their study to the pathogenic intestinal bacterium Escherichia coli (EPEC), the scientists indicate that the strategy of delaying entry into cells to ensure survival may be widespread among pathogens, possibly including the bacterial agents of meningitis and pneumonia. These newly discovered signaling pathways may, therefore, open up exciting opportunities for preventing infection.
Tyrosine-Phosphorylated Caveolin-1 Blocks Bacterial Uptake by Inducing Vav2-RhoA-Mediated Cytoskeletal Rearrangements.
Jan Peter Boettcher, Marieluise Kirchner, Yuri Churin, Alexis Kaushansky, Malvika Pompaiah, Hans Thorn, Volker Brinkmann, Gavin MacBeath, Thomas F. Meyer
PLoS Biol, 8(8): e1000457 DOI: 10.1371/journal.pbio.1000457
Link to PLoS Biol abstract