Lectins play critical roles in the immune system. The lectins on dendritic cells participate in antigen recognition and internalization and thereby serve as critical mediators of immunity. One such lectin, DC-SIGN, which mediates the beneficial process of antigen uptake for processing, can be co-opted by pathogens to suppress immune responses and promote their dissemination. For example, DC-SIGN can bind to HIV and facilitate its dissemination. It also has been shown to suppress immune responses to Mycobacterium tuberculosis. Because HIV and Mycobacterium tuberculosis are the two most significant threats to human health worldwide, it is critical to elucidate the molecular mechanisms underlying the function of DC-SIGN. The long-term goals of the proposed research are to use chemical biology to illuminate how DC-SIGN functions in signaling, antigen recognition, and antigen internalization. Insight into these processes can facilitate the design of agents to enhance the effectiveness of vaccines or prevent pathogen infection.
The specific aims of the project follow: (1) to identify non-carbohydrate, small-molecule ligands for DC- SIGN, (2) to develop chemical imaging strategies to follow DC-SIGN-mediated antigen internalization and dendritic cell migration, and (3) to develop new chemical approaches to explore bacteria-dendritic cell interactions mediated by DC-SIGN. The first specific aim focuses on providing a novel set of inhibitors of DC-SIGN. These also can serve as tools for exploring the consequences of engaging this lectin. The DC-SIGN ligands identified to date are based on carbohydrates, which bind weakly and can interact with other dendritic cell-surface lectins. We envision that non-carbohydrate-based ligands will bind to DC-SIGN with higher specificity and affinity.
In Aim 2, we shall use the ligands identified in Aim 1 to explore the consequences of antigen interaction with DC-SIGN. DC-SIGN interacts with a variety of different types of antigens (proteins, viruses, bacteria, and fungi);therefore, it is critical to understand how antigen structure influences internalization and trafficking. We shall use chemical synthesis to vary DC-SIGN ligand structure and to endow these model antigens with fluorogenic reporter groups for imaging.
Aim 3 addresses how dendritic cell internalization and processing of organisms is influenced by DC-SIGN engagement. To investigate this process, we shall chemically modify bacteria such that they display specific DC-SIGN ligands. The results of the investigations proposed in Aim 3 can provide insight into the role of DC-SIGN and offer new strategies to explore the role of specific receptors in host-pathogen interactions. Relevance. The carbohydrate-binding protein DC-SIGN is found on the surface of dendritic cells, where it functions in the immune system. In addition to its normal function in humans, DC-SIGN can be used by viruses, like HIV, to facilitate their dissemination, and by some bacteria, like those that cause tuberculosis, to suppress immune responses. Because of its role in facilitating the two diseases that cause the most deaths worldwide, how DC- SIGN works and how to control it is important. This project is aimed at identifying DC-SIGN inhibitors and using compounds that bind to DC-SIGN to study its function.

Public Health Relevance

The carbohydrate-binding protein DC-SIGN is found on the surface of dendritic cells, where it functions in the immune system. In addition to its normal function in humans, DC-SIGN can be used by viruses, like HIV, to facilitate their dissemination, and by some bacteria, like those that cause tuberculosis, to suppress immune responses. Because of its role in facilitating the two diseases that cause the most deaths worldwide, how DC-SIGN works and how to control it is important. This project is aimed at identifying DC-SIGN inhibitors and using compounds that bind to DC-SIGN to study its function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM049975-17S1
Application #
8540481
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (02))
Program Officer
Fabian, Miles
Project Start
1993-07-01
Project End
2013-04-04
Budget Start
2010-12-01
Budget End
2013-04-04
Support Year
17
Fiscal Year
2012
Total Cost
$103,992
Indirect Cost
$30,868
Name
University of Wisconsin Madison
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Wrighton, Paul J; Kiessling, Laura L (2015) Forces of Change: Mechanics Underlying Formation of Functional 3D Organ Buds. Cell Stem Cell 16:453-4
Hudson, Kieran L; Bartlett, Gail J; Diehl, Roger C et al. (2015) Carbohydrate-Aromatic Interactions in Proteins. J Am Chem Soc 137:15152-60
Bennett, Nitasha R; Zwick, Daniel B; Courtney, Adam H et al. (2015) Multivalent Antigens for Promoting B and T Cell Activation. ACS Chem Biol 10:1817-24
Sheridan, Rachael T C; Hudon, Jonathan; Hank, Jacquelyn A et al. (2014) Rhamnose glycoconjugates for the recruitment of endogenous anti-carbohydrate antibodies to tumor cells. Chembiochem 15:1393-8
Musah, Samira; Wrighton, Paul J; Zaltsman, Yefim et al. (2014) Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification. Proc Natl Acad Sci U S A 111:13805-10
Courtney, Adam H; Bennett, Nitasha R; Zwick, Daniel B et al. (2014) Synthetic antigens reveal dynamics of BCR endocytosis during inhibitory signaling. ACS Chem Biol 9:202-10
Wrighton, Paul J; Klim, Joseph R; Hernandez, Brandon A et al. (2014) Signals from the surface modulate differentiation of human pluripotent stem cells through glycosaminoglycans and integrins. Proc Natl Acad Sci U S A 111:18126-31
Fishman, Joshua M; Kiessling, Laura L (2013) Synthesis of functionalizable and degradable polymers by ring-opening metathesis polymerization. Angew Chem Int Ed Engl 52:5061-4
Kiessling, Laura L; Kraft, Matthew B (2013) Chemistry. A path to complex carbohydrates. Science 341:357-8
Kiessling, Laura L; Grim, Joseph C (2013) Glycopolymer probes of signal transduction. Chem Soc Rev 42:4476-91

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