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Downstream Signals for MyD88-Mediated Phagocytosis of Borrelia burgdorferi Can Be Initiated by TRIF and Are Dependent on PI3K¹

Ok S. Shin^*, Lloyd S. Miller, Robert L. Modlin, Shizuo Akira, Satoshi Uematsu and Linden T. Hu^2,*,

^* Department of Pathology/Immunology, Sackler School for Graduate Biomedical Studies, Tufts University, Boston, MA 02111; Tufts Medical Center, Tufts University School of Medicine, Tupper Research Institute, Division of Geographic Medicine and Infectious Diseases, Boston, MA 02111; Division of Dermatology and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

We previously have shown that MyD88 is important for uptake of Borrelia burgdorferi by bone marrow derived macrophages (BMDMs). The mechanism by which MyD88 is involved in uptake of B. burgdorferi is currently is not well characterized. Here, we report that MyD88-mediated defect in the phagocytosis of B. burgdorferi can be complemented by TLR3/Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF) activation in BMDMs from MyD88^–/– mice. This effect of TLR3/TRIF activation was not due to its induction of type I IFNs, suggesting instead a convergence of signaling pathways downstream of MyD88 and TRIF. To characterize signaling pathways involved in MyD88-mediated phagocytosis of B. burgdorferi, BMDMs were treated with specific inhibitors of MAPK, protein kinase C, JAK/STAT, or PI3K. Only inhibition of PI3K resulted in a significant decrease of B. burgdorferi uptake. Consistent with this, B. burgdorferi activation of MyD88 or TLR3/TRIF signaling resulted in increased activity of PI3K. Additionally, association of B. burgdorferi with actin-related protein (Arp2/3) complexes, which facilitate actin rearrangements during phagocytosis, was similarly reduced in MyD88^–/– BMDMs and in BMDMs treated with a PI3K inhibitor. Taken together, these findings define an essential pathway whereby downstream signals from MyD88 or TRIF converge on PI3K, which triggers actin polymerization to initiate the phagocytosis of B. burgdorferi.

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 R01AI050043 from the National Institute of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Linden T. Hu, Tufts Medical Center, 750 Washington Street, Boston, MA 02111. E-mail address: lhu{at}tuftsmedicalcenter.org

³ Abbreviations used in this paper: BMDM, bone marrow-derived macrophage; Arp2/3 complexes, actin-related protein 2/3 complexes; DN, dominant negative; MOI, multiplicity of infection; PKC, protein kinase C; qRT-PCR, quantitative RT-PCR; TRAF, TNFR-associated factor; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-β; WT, wild type.