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Infection and Immunity, June 2008, p. 2341-2351, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01600-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Distinct Roles for MyD88 and Toll-Like Receptors 2, 5, and 9 in Phagocytosis of Borrelia burgdorferi and Cytokine Induction {triangledown}

Ok S. Shin,1 Ralph R. Isberg,3 Shizuo Akira,4 Satoshi Uematsu,4 Aruna K. Behera,2* and Linden T. Hu1,2*

Department of Pathology/Immunology, Sackler School for Graduate Biomedical Studies, Tufts University, 155 Harrison Avenue, Boston, Massachusetts 02111,1 Division of Geographic Medicine and Infectious Diseases, Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111,2 Howard Hughes Medical Institute, Tufts University School of Medicine, 150 Harrison Avenue, Boston, Massachusetts 02111,3 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University 3-1, Yamada-Oka, Suita, Osaka 565-0871, Japan4

Received 4 December 2007/ Returned for modification 10 January 2008/ Accepted 19 March 2008

The contribution of Toll-like receptors (TLRs) to phagocytosis of Borrelia burgdorferi has not been extensively studied. We show that bone marrow-derived macrophages (BMDM) from MyD88–/– mice or Raw cells transfected with a dominant-negative MyD88 were unable to efficiently internalize B. burgdorferi. Knockouts of TLR2 and TLR9 or knockdown of TLR5 by small interfering RNA produced no defects in phagocytosis of B. burgdorferi. Production of inflammatory cytokines was greatly diminished in MyD88–/– BMDM but only partially affected in TLR2–/– BMDM or knockdown of TLR5 and unaffected in TLR9–/– BMDM. Cytochalasin D reduced cytokine induction, but not to the level of the MyD88–/– BMDM. Addition of cytochalasin D to TLR2–/– BMDM inhibited inflammatory responses to B. burgdorferi to the level of MyD88–/– BMDM, consistent with a role for TLR2 in both recognition of extracellular products and lysosomal sampling by TLR2 after processing of the organism. Cytochalasin D had no impact on cytokine production in cells undergoing TLR5 knockdown. These results suggest that MyD88, but not TLR2, TLR5, and TLR9, is important for the uptake of B. burgdorferi and that MyD88 affects inflammatory responses through both its effects on phagocytosis and its role in transducing signals from TLR2 and TLR5.

* Corresponding author. Mailing address: Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111. Phone: (617) 636-8498. Fax: (617) 636-3216. E-mail for A. K. Behera: abehera{at}tuftsmedicalcenter.org. E-mail for L. Hu: lhu{at}tuftsmedicalcenter.org

{triangledown} Published ahead of print on 31 March 2008.

Editor: J. B. Bliska

Infection and Immunity, June 2008, p. 2341-2351, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01600-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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