Toll-like receptors are temporally involved in host defense.
Toll-like receptors (TLRs) are evolutionarily conserved proteins that recognize microbial molecules and initiate host defense. To investigate how TLRs work together to fight infections, we tested the role of TLRs in host defense against the Gram-negative bacterial pathogen, Salmonella. We show that TLR4 is critical for early cytokine production and killing of bacteria by murine macrophages. Interestingly, later on, TLR2, but not TLR4, is required for macrophage responses. Myeloid differentiation factor 88, an adaptor protein directly downstream of TLRs, is required for both early and late responses. TLR4, TLR2, and myeloid differentiation factor 88 are involved in murine host defense against Salmonella in vivo, which correlates with the defects in host defense observed in vitro. We propose a model where the sequential activation of TLRs tailors the immune response to different microbes.
Weiss
David S
DS
Department of Microbiology and Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
Raupach
Bärbel
B
Takeda
Kiyoshi
K
Akira
Shizuo
S
Zychlinsky
Arturo
A
D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing; D000284:Administration, Oral; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics; D001770:Blood Bactericidal Activity / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000254:growth & development / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000942:Antigens, Bacterial; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors