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* Department of Microbiology and Immunology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107;
Department of Host Defense, Osaka University, Osaka, Japan;
Division of Infectious Diseases and Immunology,
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655
Bacteremia is one of the leading causes of death by infectious disease. To understand the immune mechanisms required for the rapid control of bacteremia, we studied Borrelia hermsii, a bacterial pathogen that colonizes the blood stream of humans and rodents to an extremely high density. A T cell-independent IgM response is essential and sufficient for controlling B. hermsii bacteremia. Mice deficient in Bruton’s tyrosine kinase (Btk), despite their known defect in BCR signaling, generated B. hermsii-specific IgM and resolved bacteremia, suggesting that an alternative activation or costimulatory pathway remained functional for T cell-independent B cells in Btk–/– mice. B. hermsii contains putative ligands for TLRs, and we found that mice deficient in TLR1, TLR2, or the TLR adaptor MyD88 generated anti-B. hermsii IgM with delayed kinetics and suffered more severe episodes of bacteremia. In striking contrast to the anti-B. hermsii IgM response in mice deficient only in Btk, mice deficient in both Btk and MyD88 were entirely incapable of generating B. hermsii-specific Ab or resolving bacteremia. The response to a T cell-dependent model Ag was unaffected in Btk–/– x MyD88–/– mice. These results suggest that MyD88 specifically promotes T cell-independent BCR signaling and that, in the absence of Btk, this TLR-mediated stimulation is a required component of this signal.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institute of Health Grants R01 AI065750 (to K.R.A.), R01 AI057588 (to E.L.), and R01 AI37601 (to J.M.L.).
2 Address correspondence and reprint requests to Dr. Kishore R. Alugupalli, Department of Microbiology and Immunology, Thomas Jefferson University, 233 South 10th Street, BLSB 726, Philadelphia, PA 19107. E-mail address: kishore.alugupalli{at}mail.jci.tju.edu
3 E.L. and J.M.L. contributed equally to this study.
4 Abbreviations used in this paper: TI, T cell independent; TD, T cell dependent; FO, follicular; MZ, marginal zone; DKO, double knockout; NP-CGG, nitrophenyl-conjugated-chicken gammaglobulin; wt, wild type.
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