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

Nature Medicine volume 8, pages 878–884 (2002)Cite this article

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-α 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.

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Figure 1: Characterization of individuals with low titers of antibodies against OspA after immunization with OspA lipoprotein.
Figure 2: TLR2 surface protein expression in low and normal responders.
Figure 3: Responses of wild-type (WT) and TLR2−/− mice to OspA immunization and B. burgdorferi infection.
Figure 4: Cooperation of TLR1 and TLR2 in OspA recognition.
Figure 5: Generation of TLR1−/− mice.
Figure 6: TLR1 is critical to the recognition of OspA.

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Acknowledgements

We thank T. Deshefy-Longhi, S. Samanta and D. Beck for assistance, and F. Manzo for assistance with manuscript preparation. This work was supported by grants from the US National Institutes of Health, and an Arthritis Foundation Biomedical Science Grant (RAF). L.A. received a Human Frontier Science Program postdoctoral long-term fellowship, E.F. received a Clinical-Scientist Award in Translational Research from the Burroughs Wellcome Fund, R.M. is supported by a Searl Scholarship, and R.M. is an Assistant Investigator and R.A.F. is an Investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Lena Alexopoulou, Venetta Thomas, Markus Schnare, Ruslan Medzhitov, Erol Fikrig and Richard A. Flavell: These authors contributed equally to this work.

Authors and Affiliations

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

    Lena Alexopoulou, Markus Schnare, Ruslan Medzhitov & Richard A. Flavell

  2. Department of Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT

    Venetta Thomas, Robert T. Schoen & Erol Fikrig

  3. SmithKline Beecham Biologicals, Rixensart, Belgium

    Yves Lobet

  4. Department of Biology, University of North Carolina at Charlotte, Charlotte, NC

    Juan Anguita

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Correspondence to Erol Fikrig or Richard A. Flavell.

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E.F. and R.F. receive royalties from Yale University for a license agreement between Yale and SmithKline Beecham (GlaxoSmithKline) for an OspA-based vaccine.

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Alexopoulou, L., Thomas, V., Schnare, M. et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8, 878–884 (2002). https://doi.org/10.1038/nm732

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