title: Evasion of human innate immunity without antagonizing TLR4 by mutant Salmonella enterica serovar Typhimurium having penta-acylated lipid A.
abstract: Modification of a lipid A moiety in Gram-negative bacterial LPS to a less acylated form is thought to facilitate bacterial evasion of host innate immunity, thereby enhancing pathogenicity. The contribution of less-acylated lipid A to interactions of whole bacterial cells with host cells (especially in humans) remains unclear. Mutant strains of Salmonella enterica serovar Typhimurium with fewer acylated groups were generated. The major lipid A form in wild-type (WT) and the mutant KCS237 strain is hexa-acylated; in mutant strains KCS311 and KCS324 it is penta-acylated; and in KCS369 it is tetra-acylated. WT and KCS237 formalin-killed and live bacteria, as well as their LPS, strongly stimulated production of pro-inflammatory cytokines in human U937 cells; this stimulation was suppressed by TLR4 suppressors. LPS of other mutants produced no agonistic activity, but strong antagonistic activity, while their formalin-killed and live bacteria preparations had weak agonistic and no antagonistic activity. Moreover, these less-acylated mutants had increased resistance to phagocytosis by U937 cells. Our results indicate that a decrease of one acyl group (from six to five) is enough to allow Salmonella to evade human innate immunity and that the antagonistic activity of less-acylated lipid A is not utilized for this evasion.
authors.affiliation: Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. mmatsuur@mb.med.kyoto-u.ac.jp
authors.forename: Motohiro
authors.initials: M
authors.lastname: Matsuura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Masao
authors.initials: M
authors.lastname: Mitsuyama
mesh_terms: D000107:Acetylation; D019138:Antibodies, Blocking / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008050:Lipid A / Q000235:genetics / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D009154:Mutation / Q000235:genetics; D012485:Salmonella typhi / Q000276:immunology* / Q000472:pathogenicity; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014435:Typhoid Fever / Q000276:immunology*; D020298:U937 Cells
chemical_list: D019138:Antibodies, Blocking; D016207:Cytokines; D018836:Inflammation Mediators; D008050:Lipid A; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4