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Decreased Pathology and Prolonged Survival of Human DC-SIGN Transgenic Mice during Mycobacterial Infection¹

Martin Schaefer^2,*, Norbert Reiling^2,, Cornelia Fessler, Johannes Stephani^*, Ichiro Taniuchi^#,**, Farahnaz Hatam^,#, Ali Oender Yildirim^¶, Heinz Fehrenbach^¶, Kerstin Walter, Juergen Ruland, Hermann Wagner^*, Stefan Ehlers^3,4,,|| and Tim Sparwasser^3,4,*,#

^* Institute for Medical Microbiology, Immunology, and Hygiene and Third Medical Department, Klinikum rechts der Isar, Technische Universität München, Munich; Division of Molecular Infection Biology, Research Center Borstel, Borstel; Experimental Rheumatology, Medical Clinic Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin; ^¶ Clinical Research Group "Chronic Airway Diseases," Medical Faculty, Philipps University, Marburg; ^|| Molecular Inflammation Medicine, Christian-Albrechts-University, Kiel, Germany; ^# Howard Hughes Medical Institute, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016; and ^** Research Center for Allergy and Immunology, the Institute of Physical and Chemical Research, Yokohama, Japan

Dendritic cell (DC)-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN: CD209) is a C-type lectin that binds ICAM-2,3 and various pathogens such as HIV, helicobacter, and mycobacteria. It has been suggested that Mycobacterium tuberculosis, the causative agent of pulmonary tuberculosis, interacts with DC-SIGN to evade the immune system. To directly analyze the role of human DC-SIGN during mycobacterial infection, we generated conventional transgenic (tg) mice (termed "hSIGN") using CD209 cDNA under the control of the murine CD11c promoter. Upon mycobacterial infection, DCs from hSIGN mice produced significantly less IL-12p40 and no significant differences were be observed in the secretion levels of IL-10 relative to control DCs. After high dose aerosol infection with the strain M. tuberculosis H37Rv, hSIGN mice showed massive accumulation of DC-SIGN⁺ cells in infected lungs, reduced tissue damage and prolonged survival. Based on our in vivo data, we propose that instead of favoring the immune evasion of mycobacteria, human DC-SIGN may have evolved as a pathogen receptor promoting protection by limiting tuberculosis-induced pathology.

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 in part by the Deutsche Forschungsgemeinschaft (SP 615/4-2 and SFB/TR22 to T.S., GRK288, A6 to N.R. and S.E., and SFB 470 C9 to S.E.) and the German National Genome Research Network (01GS0412 to S.E.).

² M.S. and N.R. contributed equally to this work.

³ S.E. and T.S. are joint senior authors.

⁴ Address correspondence and reprint requests to Dr. Tim Sparwasser, Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universität München, Trogerstrasse 30, 81675 Munich, Germany. E-mail address: tim.sparwasser{at}lrz.tum.de or Dr. Stefan Ehlers, Divison of Molecular Infection Biology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany. E-mail address: sehlers{at}fz-borstel.de

⁵ Abbreviations used in this paper: Mtb, Mycobacterium tuberculosis; DC, dendritic cell; DC-SIGN, DC-specific intercellular adhesion molecule-3 grabbing nonintegrin; ManLAM, mycobacterial mannosylated LAM; SNP, single nucleotide polymorphism; hSIGN, human DC-SIGN; tg, transgenic; GM-DC, GM-CSF-derived DC; BMDC, bone marrow-derived dendritic cell; WT, wild type; MMP, matrix metalloproteinase; SUR, systematic uniform random; MHCII, MHC class II; BCG, Mycobacterium bovis Bacillus Calmette Guérin.

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