TLR4-dependent adjuvant activity of Neisseria meningitidis lipid A

Abstract

The adjuvant activity of Neisseria meningitidis serogroup B lipopoly(oligo)saccharide (LOS) from wild-type and genetically-defined LOS mutants and unglycosylated meningococcal lipid A was assessed in C3H/HeN and C3H/HeJ mice. Meningococcal lipid A, a weak agonist for TLR4/MD-2 in human macrophages, was found to have adjuvant activity similar to that of wild-type and KDO 2 -lipid A LOS in C3H/HeN mice. All meningococcal LOS structures as adjuvants induced high titers of IgG1, IgG2a and IgG2b but very little IgG3 to OMP compared to no adjuvant PBS controls. In addition, induced OMP antibodies were shown to have high bactericidal activity against serogroup B meningococci. Purified LOS and lipid A structures failed to induce any adjuvant activity in C3H/ HeJ mice indicating that meningococcal LOS as an adjuvant was TLR4-dependent. Unglycosylated meningococcal lipid A because of its weak agonist activity for human macrophages and retention of adjuvant activity may be a candidate for use in serogroup B meningococcal OMP and OMV vaccines and for use as an adjuvant in other vaccines.

Pseudomonas aeruginosa Outer Membrane Vesicles Modulate Host Immune Responses by Targeting the Toll-Like Receptor 4 Signaling Pathway

“…The literature also showed that OMVs generated from a wide range of bacteria can elicit the production of various cytokines by epithelial cells (48,49). In Neisseria meningitides, LPS acts as an adjuvant to the components of vesicles and can profoundly modulate inflammatory responses of macrophages in a TLR4-dependent manner (21,22,25). The current study provided a detailed in vitro and in vivo mechanism for the stimulation of proinflammatory mediators by P. aeruginosa OMVs that was TLR4 dependent (Fig.…”

“…Therefore, the activation of the host immune response elicited by P. aeruginosa OMVs is dependent primarily on LPS via the TLR4 signaling pathway but requires an intact membrane struc- Our study provides further evidence that development of a pseudomonal vaccine based on OMVs of P. aeruginosa is a promising approach. Vaccines that effectively prevent P. aeruginosa pulmonary infections could be very useful, and previous studies suggested that LPS is an influential effector in the development of vaccines in mice (20)(21)(22)51). Ramphal et al also showed that Pseudomonas LPS is not a key virulence factor in acute pneumonia and thus can be used as an adjuvant to trigger a prominent proinflammatory response and effectively defend the lung from P. aeruginosa infection (52).…”

“…Previous research reported that OMVs could elicit heightened innate immune responses by the combined sensing of both LPS and protein components (14,(20)(21)(22). OMVs were shown to be promising for development of vaccines against infection by the corresponding bacteria (21)(22)(23)(24)(25)(26)(27).…”

“…OMVs were shown to be promising for development of vaccines against infection by the corresponding bacteria (21)(22)(23)(24)(25)(26)(27). Remarkably, vaccines developed based on Neisseria lactamica OMVs were shown to render effective protection against meningococcal infection and underwent a phase I clinical trial for safety and immunogenicity studies with adult volunteers (27,28).…”

Identification of Genes Particularly Sensitive to Lipopolysaccharide (LPS) in Human Monocytes Induced by Wild-Type versus LPS-DeficientNeisseria meningitidisStrains

“…The different clinical presentations are the consequences of a variable propensity of N. meningitidis to multiply in the circulation of the individual patient and to penetrate into the subarachnoid space to cause meningitis after the initial bacteremic phase (3,6,8,41,49,53). There is a close correlation between the real number of meningococci in plasma or cerebrospinal fluid and the concentration of meningococcal lipopolysaccharide (LPS) in these compartments (32).…”