Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice

Lena Alexopoulou; Venetta Thomas; Markus Schnare; Yves Lobet; Juan Anguita; Robert T Schoen; Ruslan Medzhitov; Erol Fikrig; Richard A Flavell

doi:10.1038/nm732

Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice

Nat Med. 2002 Aug;8(8):878-84. doi: 10.1038/nm732. Epub 2002 Jul 1.

Authors

Lena Alexopoulou¹, Venetta Thomas, Markus Schnare, Yves Lobet, Juan Anguita, Robert T Schoen, Ruslan Medzhitov, Erol Fikrig, Richard A Flavell

Affiliation

¹ Section of Immunobiology and the Howard Hughes Medical Institute, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

PMID: 12091878
DOI: 10.1038/nm732

Abstract

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.

Publication types

Clinical Trial
Clinical Trial, Phase III
Multicenter Study
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Antibodies, Bacterial / blood*
Antigens, Surface / immunology*
Bacterial Outer Membrane Proteins / immunology*
Bacterial Vaccines
Borrelia burgdorferi / chemistry
Borrelia burgdorferi / immunology*
Cell Separation
Cells, Cultured
Drosophila Proteins*
Humans
Interleukins / metabolism
Lipoproteins / immunology
Lipoproteins / metabolism
Lyme Disease Vaccines / immunology*
Macrophages / immunology
Macrophages / metabolism
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Mice
Mice, Knockout
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism*
Signal Transduction
Toll-Like Receptor 1
Toll-Like Receptor 2
Toll-Like Receptors

Substances

Antibodies, Bacterial
Antigens, Surface
Bacterial Outer Membrane Proteins
Bacterial Vaccines
Drosophila Proteins
Interleukins
Lipoproteins
Lyme Disease Vaccines
Membrane Glycoproteins
OspA protein
Receptors, Cell Surface
TLR2 protein, human
Toll-Like Receptor 1
Toll-Like Receptor 2
Toll-Like Receptors