Protective Role of Toll-like Receptor 4 in Experimental Gonococcal Infection of Female Mice

Neisseria gonorrhoeae is a common bacterial sexually transmitted infection. Like all Gram-negative bacteria, the outer membrane of the gonococcus is rich in endotoxin, a known ligand for Toll-like receptor (TLR)-4. However, the role of endotoxin and its cognate receptor TLR4 in the mucosal response to acute gonococcal infection in the genital tract of women is unclear. To test this, we examined the course of infection following vaginal inoculation of Neisseria gonorrhoeae in mice carrying the Lps(d) mutation in Tlr4, which renders them unresponsive to endotoxin. While there was no difference in the duration of colonization, the Lps(d) mice had a significantly higher peak bacterial burden which coincided with a massive polymorphonuclear cell influx and the concomitant upregulation of a subset of inflammatory cytokine and chemokine markers. Notably, infected Lps(d) mice showed a decrease in IL-17, suggesting Th17 responses are more dependent on TLR4 signaling in vivo. Defective PMN-mediated and complement-independent serum killing of gonococci in Lps(d) mice was also observed and may account for the increased bacterial burden. This is the first in vivo evidence that TLR4-regulated factors modulate the early inflammatory response to gonococcal infection in the female reproductive tract and control bacterial replication.