The clinical presentation of meningococcal disease is closely related to the number of meningococci in the circulation. This study aimed to examine the activation of the innate immune system after being exposed to increasing and clinically relevant concentrations of meningococci. We incubated representative Neisseria meningitidis serogroup B (ST-32) and serogroup C (ST-11) strains and a lipopolysaccharide (LPS)-deficient mutant (the 44/76 lpxA mutant) in human serum and whole blood and measured complement activation and cytokine secretion and the effect of blocking these systems. HEK293 cells transfected with Toll-like receptors (TLRs) were examined for activation of NF-kappaB. The threshold for cytokine secretion and activation of NF-kappaB was 10(3) to 10(4) meningococci/ml. LPS was the sole inflammation-inducing molecule at concentrations up to 10(5) to 10(6) meningococci/ml. The activation was dependent on TLR4-MD2-CD14. Complement contributed to the inflammatory response at >or=10(5) to 10(6) meningococci/ml, and complement activation increased exponentially at >or=10(7) bacteria/ml. Non-LPS components initiated TLR2-mediated activation at >or=10(7) bacteria/ml. As the bacterial concentration exceeded 10(7)/ml, TLR4 and TLR2 were increasingly activated, independent of CD14. In this model mimicking human disease, the inflammatory response to N. meningitidis was closely associated with the bacterial concentration. Therapeutically, CD14 inhibition alone was most efficient at a low bacterial concentration, whereas addition of a complement inhibitor may be beneficial when the bacterial load increases.