Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice.
The Lyme disease vaccine is based on the outer-surface lipoprotein (OspA) of the pathogen Borrelia burgdorferi, and 95% of vaccine recipients develop substantial titers of antibodies against OspA. Here, we identified seven individuals with very low antibody titers after vaccination (low responders). The macrophages of low responders produced less tumor necrosis factor-alpha and interleukin-6 after OspA stimulation and had lower cell-surface expression of Toll-like receptor (TLR) 1 as compared to normal cells, but normal expression of TLR2. TLRs activate innate responses to pathogens, and TLR2 recognizes lipoproteins and peptidoglycan (PGN). After OspA immunization, mice genetically deficient in either TLR2 (TLR2(-/-)) or TLR1 (TLR1(-/-)) produced low titers of antibodies against OspA. Notably, macrophages from TLR2(-/-) mice were unresponsive to OspA and PGN, whereas those from TLR1(-/-) mice responded normally to PGN but not to OspA. These data indicate that TLR1 and TLR2 are required for lipoprotein recognition and that defects in the TLR1/2 signaling pathway may account for human hyporesponsiveness to OspA vaccination.
Alexopoulou
Lena
L
Section of Immunobiology and the Howard Hughes Medical Institute, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
Thomas
Venetta
V
Schnare
Markus
M
Lobet
Yves
Y
Anguita
Juan
J
Schoen
Robert T
RT
Medzhitov
Ruslan
R
Fikrig
Erol
E
Flavell
Richard A
RA
D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood*; D000954:Antigens, Surface / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology*; D001428:Bacterial Vaccines; D025065:Borrelia burgdorferi / Q000737:chemistry / Q000276:immunology*; D002469:Cell Separation; D002478:Cells, Cultured; D029721:Drosophila Proteins; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008074:Lipoproteins / Q000276:immunology / Q000378:metabolism; D022123:Lyme Disease Vaccines / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
D000907:Antibodies, Bacterial; D000954:Antigens, Surface; D001425:Bacterial Outer Membrane Proteins; D001428:Bacterial Vaccines; D029721:Drosophila Proteins; D007378:Interleukins; D008074:Lipoproteins; D022123:Lyme Disease Vaccines; D008562:Membrane Glycoproteins; C072045:OspA protein; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors