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Infection and Immunity, June 2004, p. 3195-3203, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3195-3203.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation in Borrelia burgdorferi-Infected Mice

Nengyin Liu,1 Ruth R. Montgomery,1 Stephen W. Barthold,2 and Linda K. Bockenstedt1*

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut,1 Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, Davis, California2

Received 12 December 2003/ Returned for modification 26 January 2004/ Accepted 11 February 2004

The spirochete Borrelia burgdorferi causes acute inflammation in mice that resolves with the development of pathogen-specific adaptive immunity. B. burgdorferi lipoproteins activate innate immune cells via Toll-like receptor 2 (TLR2), but TLR2-deficient mice are not resistant to B. burgdorferi-induced disease, suggesting the involvement of other TLRs or non-TLR mechanisms in the induction of acute inflammation. For this study, we used mice that were deficient in the intracellular adapter molecule myeloid differentiation antigen 88 (MyD88), which is required for all TLR-induced inflammatory responses, to determine whether the interruption of this pathway would alter B. burgdorferi-induced disease. Infected MyD88–/– mice developed carditis and arthritis, similar to the disease in wild-type (WT) mice analyzed at its peak (days 14 and 28) and during regression (day 45). MyD88–/– macrophages produced tumor necrosis factor alpha only when spirochetes were opsonized, suggesting a role for B. burgdorferi-specific antibody in disease expression. MyD88–/– mice produced stronger pathogen-specific Th2-dependent immunoglobulin G1 (IgG1) responses than did WT mice, and their IgM titers remained significantly elevated through 90 days of infection. Despite specific antibodies, the pathogen burden was 250-fold higher in MyD88–/– mice than in WT mice 45 days after infection; by 90 days of infection, the pathogen burden had diminished substantially in MyD88–/– mice, but it was still elevated compared to that in WT mice. The elevated pathogen burden may be explained in part by the finding that MyD88–/– peritoneal macrophages could ingest spirochetes but degraded them more slowly than WT macrophages. Our results show that MyD88-dependent signaling pathways are not required for B. burgdorferi-induced inflammation but are necessary for the efficient control of the pathogen burden by phagocytes.

* Corresponding author. Mailing address: S-525C The Anlyan Center, Yale University School of Medicine, 300 Cedar St., P.O. Box 208031, New Haven, CT 06520-8031. Phone: (203) 785-2454. Fax: (203) 785-7063. E-mail: linda.bockenstedt{at}yale.edu.

Editor: D. L. Burns

Infection and Immunity, June 2004, p. 3195-3203, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3195-3203.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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