A Lipopolysaccharide-Deficient Mutant of Neisseria meningitidis Elicits Attenuated Cytokine Release by Human Macrophages and Signals via Toll-like Receptor (TLR) 2 but Not via TLR4/MD2

• Published in: The Journal of infectious diseases 2001-01, Vol.183 (1), p.89-96
• Main Authors: Pridmore, Alison C., Wyllie, David H., Abdillahi, Fatumo, Steeghs, Liana, van der Ley, Peter, Dower, Steven K., Read, Robert C.
• Format: Article
• Language: English
• Subjects: Acyltransferases - deficiency; Acyltransferases - genetics; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria; Biological and medical sciences; Cultured cells; Cytokines; Cytokines - analysis; Drosophila Proteins; HeLa Cells; Human viral diseases; Humans; Infections; Infectious diseases; Interleukin-8 - analysis; Lipopolysaccharide Receptors - biosynthesis; Lipopolysaccharide Receptors - genetics; lipopolysaccharides; Lipopolysaccharides - analysis; Macrophages; Macrophages - immunology; Macrophages - microbiology; Major Articles; Medical sciences; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Mutation; Neisseria meningitidis; Neisseria meningitidis - genetics; Pharmacology. Drug treatments; Receptors; Receptors, Cell Surface - biosynthesis; Receptors, Cell Surface - genetics; TLR2 protein; Toll like receptors; Toll-Like Receptor 2; Toll-Like Receptor 4; Transfection; tumor necrosis factor-^a; Tumor Necrosis Factor-alpha - analysis; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/317647

Meningococcal disease severity correlates with circulating concentrations of lipopolysaccharide (LPS) and proinflammatory cytokines. Disruption of the lpxA gene of Neisseria meningitidis generated a viable strain that was deficient of detectable LPS. The potency of wild-type N. meningitidis to elicit tumor necrosis factor (TNF)—α production by human monocyte-derived macrophages was ∼ 10-fold greater than that of the lpxA mutant. Killed wild-type N. meningitidis and its soluble products induced interleukin (IL)—8 and TNF-α secretion by transfected HeLa cells expressing Toll-like receptor (TLR) 4/MD2, but the lpxA mutant was inactive via this pathway. In contrast, both strains induced IL-8 promoter activity in TLR2-transfected HeLa cells. These data provide evidence that N. meningitidis contains components other than LPS that can elicit biological responses via pathways that are independent of the TLR4/MD2 receptor system, and TLR2 is one of these alternate pathways. These findings have implications for future therapeutic strategies against meningococcal disease on the basis of the blockade of TLRs and the modulation of LPS activity.