OPEN ORIGINAL ARTICLE Host Langerin (CD207) is a receptor for Yersinia pestis phagocytosis and promotes dissemination Kun Yang 1 , Chae G Park 2 , Cheolho Cheong 3 , Silvia Bulgheresi 4 , Shusheng Zhang 5 , Pei Zhang 5 , Yingxia He 1 , Lingyu Jiang 1 , Hongping Huang 6 , Honghui Ding 1 , Yiping Wu 7 , Shaogang Wang 8 , Lin Zhang 9 , Anyi Li 10 , Lianxu Xia 11 , Sara S Bartra 12 , Gregory V Plano 12 , Mikael Skurnik 13 , John D Klena 14 and Tie Chen 1 Yersinia pestis is a Gram-negative bacterium that causes plague. After Y. pestis overcomes the skin barrier, it encounters antigen-presenting cells (APCs), such as Langerhans and dendritic cells. They transport the bacteria from the skin to the lymph nodes. However, the molecular mechanisms involved in bacterial transmission are unclear. Langerhans cells (LCs) express Langerin (CD207), a calcium-dependent (C-type) lectin. Furthermore, Y. pestis possesses exposed core oligosaccharides. In this study, we show that Y. pestis invades LCs and Langerin-expressing transfectants. However, when the bacterial core oligosaccharides are shielded or truncated, Y. pestis propensity to invade Langerhans and Langerin-expressing cells decreases. Moreover, the interaction of Y. pestis with Langerin-expressing transfectants is inhibited by purified Langerin, a DC-SIGN (DC-specific intercellular adhesion molecule 3 grabbing nonintegrin)-like molecule, an anti-CD207 antibody, purified core oligosaccharides and several oligosaccharides. Furthermore, covering core oligosaccharides reduces the mortality associated with murine infection by adversely affecting the transmission of Y. pestis to lymph nodes. These results demonstrate that direct interaction of core oligosaccharides with Langerin facilitates the invasion of LCs by Y. pestis. Therefore, Langerin-mediated binding of Y. pestis to APCs may promote its dissemination and infection. Immunology and Cell Biology (2015) 93, 815–824; doi:10.1038/icb.2015.46 Yersinia pestis, a Gram-negative bacterium, is the causative agent of bubonic plague, passed into the annals of history as Black Death epidemics. 1,2 A hallmark of plague is the rapid dissemination of Y. pestis, which leads to systemic infection in susceptible individuals. 3,4 Many Gram-negative bacterial pathogens contain lipopolysacchar- ides, which consist of three structural regions: (i) the lipid A backbone, (ii) core oligosaccharides, and (iii) the O-antigen (Figure 1). Gram- negative bacteria are classified as smooth or rough based on the presence or absence of the O-antigen, respectively. Rough Gram- negative bacteria bear a shortened lipopolysaccharides—referred to as lipooligosaccharides (LOS)—of which the oligosaccharide core is exposed to the extracellular environment. Innate immune system functions are initiated in the skin by antigen-presenting cells (APCs) such as dendritic cells (DCs), or a subset of immature APCs, 5,6 such as Langerhans cells (LCs). APCs either phagocytose and kill invading pathogens or deliver the pathogens to other types of host immune cells for further elimination. APCs in the skin express at least three immunoreceptors that belong to the calcium-dependent (C-type) lectin family: DC-specific intercellular adhesion molecule 3 grabbing nonintegrin (DC-SIGN, CD209), DEC-205 (CD205), and Langerin (CD207). Human LCs (hLCs) mostly express Langerin but do not express DC-SIGN. 7 Pathogens such as HIV exploit DC-SIGN-mediated uptake by APCs to efficiently disseminate throughout a host, travelling to the host’s lymph nodes. 8,9 On the other hand, human Langerin (hLangerin; CD207), an innate immune receptor for HIV-1 on LCs, may function as a natural barrier to the transmission of HIV-1 and certain viruses. 10–12 In this study, we investigated the interaction between Langerin and Y. pestis core oligosaccharides. Our results suggest that after over- coming the first line of host defence (the skin) via a fleabite, Y. pestis 1 Department of Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 2 Laboratory of Immunology, Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; 3 Institut de Recherches Cliniques de Montréal (IRCM), Montreal, Quebec, Canada; 4 Department of Ecogenomics and Systems Biology, University of Vienna, Vienna, Austria; 5 Department of Biomedical Science, University of Illinois at Chicago, Rockford, IL, USA; 6 The Center for Experimental Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 7 Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 8 Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 9 Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 10 The Animal Experimental Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 11 Department of Zoonotic Diseases, National Institute for Communicable Diseases Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China; 12 Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA; 13 Department of Bacteriology and Immunology, Research Programs Unit, Immunobiology, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland and 14 The School of Basic Medical Sciences, Peking University, Beijing, China Correspondence: Dr T Chen, Department of Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095, Jiefang Avenue, Wuhan, Hubei 430030, China. E-mail: chentie@hust.edu.cn Received 4 July 2014; revised 24 March 2015; accepted 25 March 2015; accepted article preview online 1 April 2015; advance online publication, 21 April 2015 Immunology and Cell Biology (2015) 93, 815–824 & 2015 Australasian Society for Immunology Inc. All rights reserved 0818-9641/15 www.nature.com/icb