Abstract
Many pathogenic bacteria cause local infections but occasionally invade into the blood stream, often with fatal outcome. Very little is known about the mechanism underlying the switch from local to invasive infection. In the case of Neisseria gonorrhoeae, phase variable type 4 pili (T4P) stabilize local infection by mediating microcolony formation and inducing anti-invasive signals. Outer membrane porin PorBIA, in contrast, is associated with disseminated infection and facilitates the efficient invasion of gonococci into host cells. Here we demonstrate that loss of pili by natural pilus phase variation is a prerequisite for the transition from local to invasive infection. Unexpectedly, both T4P-mediated inhibition of invasion and PorBIA-triggered invasion utilize membrane rafts and signaling pathways that depend on caveolin-1-Y14 phosphorylation (Cav1-pY14). We identified p85 regulatory subunit of PI3 kinase (PI3K) and phospholipase Cγ1 as new, exclusive and essential interaction partners for Cav1-pY14 in the course of PorBIA-induced invasion. Active PI3K induces the uptake of gonococci via a new invasion pathway involving protein kinase D1. Our data describe a novel route of bacterial entry into epithelial cells and offer the first mechanistic insight into the switch from local to invasive gonococcal infection.
Highlights
The human-specific Gram-negative bacterium Neisseria gonorrhoeae is the cause of the sexually-transmitted disease gonorrhea
Whereas pili constitute adhesive structures leading to localized infections, the natural loss of piliation unblocks a hitherto unidentified signaling cascade initiated by the interaction of an outer membrane porin and a eukaryotic scavenger receptor
Since internalization signals for scavenger receptors have not been identified so far, we speculated that the 388 amino acids long scavenger receptor expressed by endothelial cells (SREC-I) cytoplasmic domain (CD) and phosphorylation of amino acid residues might play a role in signal transduction processes leading to the engulfment of PorBIAexpressing gonococci
Summary
The human-specific Gram-negative bacterium Neisseria gonorrhoeae is the cause of the sexually-transmitted disease gonorrhea. Within the 11 members of the Opa protein family, the Opa protein binds to heparan sulfate proteoglycans (HSPG) [8,9] or fibronectin and integrins [10] whereas all other Opa proteins (Opa51-60) target members of the carcinoembryonic antigen-related cellular adhesion molecules (CEACAM; for review see [11]). Another route to enter primary cervical epithelial cells requires the cooperative binding of the major outer membrane protein PorB, pili and lipooligosaccharide to the complement receptor type 3 [12,13]. Entry of N. gonorrhoeae into nonprofessional phagocytes is mediated by PorB subtype A (PorBIA)
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