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Infection and Immunity, July 2009, p. 2925-2931, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.00004-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Lipopolysaccharide-Trap-Fc, a Multifunctional Agent To Battle Gram-Negative Bacteria{triangledown}

Philipp Groß,* Katharina Brandl,{dagger} Christine Dierkes, Jürgen Schölmerich, Bernd Salzberger, Thomas Glück,{ddagger} and Werner Falk

Department of Internal Medicine I, University Hospital Regensburg, 93042 Regensburg, Germany

Received 2 January 2009/ Returned for modification 27 February 2009/ Accepted 27 April 2009

The family of Toll-like receptors (TLRs) plays a pivotal role in host defense against pathogens. However, overstimulation of these receptors may lead to uncontrolled general inflammation and eventually to systemic organ dysfunction or failure. With the intent to control overwhelming inflammation during gram-negative bacterial sepsis, we constructed soluble fusion proteins of the lipopolysaccharide (LPS)-receptor complex to modulate TLR signaling in multiple ways. The extracellular domain of mouse TLR4 and mouse myeloid differentiation factor 2 (MD-2) fusions (LPS-Trap) were linked to human immunoglobulin G Fc domains (LPS-Trap-Fc). In addition to the ability to bind LPS or gram-negative bacteria and to inhibit interleukin-6 secretion of monocytic cells after LPS treatment, LPS-Trap-Fc was able to opsonize fluorescent Escherichia coli particles. This led to enhancement of phagocytosis by monocytic cells which was strictly dependent on the presence of the Fc region. Moreover, only LPS-Trap-Fc- and not LPS-Trap-coated bacteria were sensitized to complement killing. Therefore, LPS-Trap-Fc not only neutralizes LPS but also, after binding to bacteria, enhances phagocytosis and complement-mediated killing and could thus act as a multifunctional agent to fight gram-negative bacteria in vivo.

* Corresponding author. Mailing address: Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany. Phone: 49-941-944-7124. Fax: 49-941-944-7123. E-mail: philipp.gross{at}klinik.uni-r.de

{triangledown} Published ahead of print on 11 May 2009.

Editor: A. J. Bäumler

{dagger} Present address: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037.

{ddagger} Present address: Department of Internal Medicine, Kreisklinik Trostberg, 83308 Trostberg, Germany.

Infection and Immunity, July 2009, p. 2925-2931, Vol. 77, No. 7
0019-9567/09/$08.00+0     doi:10.1128/IAI.00004-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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