SI · Structural and functional characterization of the ICOS/ICOSL immune complex
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2018-08-01 → 2021-12-31
- Финансиране от ЕС
- 224 683 €
- Участници
- 2
- Схема
- MSCA-IF-GF
Линиите свързват координатора с партньорите.
Накратко на български
Структурата на имунния комплекс ICOS/ICOS-L разкрива как се активират Т-клетките и се развиват В-клетките. Това помага за подобряване на хуморалния имунен отговор при разработването на ваксини и имунотерапия.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Structural and functional characterization of the ICOS/ICOSL immune complex
The work described in the proposal and now published in Nature Communications describes a breakthrough in the structural characterization of the T cell co-receptor inducible co-stimulator (ICOS) and its ligand ICOS-L. Therefore, it represents a significant advance for understanding the molecular events involved in promoting T cell activation and affinity maturation of B cells. and offers yet unexplored opportunities to modulate germinal centers and consequently, the strength of humoral responses in vaccine research and immunotherapy. This work has been also presented in the 29th annual Buffalo-Hamilton-Toronto (BHT) crystallography-CryoEM symposium through an oral communication and at a virtual lecture at the University of Tokyo. Due to the acquired knowledge in antibody engineering during this project, I have joined the efforts to fight COVID19 through the development of potent and broad antibody-like particles against SARS-CoV-2 (published in Nature Communications). Due to the therapeutic potential of this technology, I then applied this strategy to target HIV, arguably the most challenging virus due to its high genetic diversity (published in PNAS). In addition, I have set up serological detection methods to analyze SARS-CoV-2 induced immune response that led to two important collaborations that culminated in two scientific publications (Sci. Adv. and Sci. Rep.). Publications: 1. Edurne Rujas; Hong Ciu; Taylor Sicard; Anthony Semesi; Jean-Philippe Julien. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. Nat. Commun.11 - 5066, 2020. 2. Edurne Rujas, Hong Cui, Jonathan Burnie, Clare Burn Aschner, Tiantian Zhao, Sara Insausti, Krithika Muthuraman, Anthony Semesi, Jasper Ophel, Jose Luis Nieva, Michael S. Seaman, Christina Guzzo, Bebhinn Treanor, Jean-Philippe Julien. Engineering pan-HIV-1 neutralization breadth and outstanding potency by multi-specific antibody avidity. PNAS, In Press. 2021. 3. Edurne Rujas*, Daniel P. Leaman, Sara Insausti, Pablo Carravilla, Miguel Garc a-Porras, Eneko Largo, Izaskun Morillo, Rub n S nchez-Eugenia, Lei Zhang, Hong Cui, Ibon Iloro, F lix Elortza, Jean-Philippe Julien, Christian Eggeling, Michael B. Zwick, Jose M. M. Caaveiro*, Jos L*. Nieva. Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile. iScience. 24 - 9, 2021. *Corresponding author 4. Moustafa T. Mabrouk, Kevin Chiem, Edurne Rujas, Wei-Chiao Huang, Dushyant Jahagirdar, Breandan Quinn, Meera Surendran Nair, Ruth H Nissly, Victoria S. Cavener, Nina R. Boyle, Ty A. Sornberger, Suresh V. Kuchipudi, Joaquin Ortega, Jean-Philippe Julien, Luis Martinez-Sobrido, Jonathan Lovell. Lyophilized, Thermostable Spike or RBD Immunogenic Liposomes Induce Protective Immunity Against SARS-CoV-2 in Mice. Sci. Adv. 7 (49), 2021. 5. Michael G. Sugiyama, Haotian Cui, Dar’ya S. Redka, Mehran Karimzadeh, Edurne Rujas, Hassaan Maan, Sikander Hayat, Kyle Cheung, Rahul Misra, Joseph B. McPhee, Russell D. Viirre, Andrew Haller, Roberto J. Botelho, Raffi Karshafian, Sarah A. Sabatinos, Gregory D. Fairn, Seyed Ali Madani Tonekaboni, Andreas Windemuth, Jean-Philippe Julien, Vijay Shahani, Stephen S. MacKinnon, Bo Wang, Costin N. Antonescu. Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease. Sci Rep. 11(1) 23315, 2021. 6. Edurne Rujas, Iga Kucharska, Yong Zi Tan, Samir Benlekbir, Hong Cui, Tiantian Zhao, Gregory A. Wasney, Patrick Budylowski, Furkan Guvenc, Jocelyn C. Newton, Taylor Sicard, Anthony Semesi, Krithika Muthuraman, Amy Nouanesengsy, Clare Burn Aschner, Katherine Prieto, Stephanie A. Bueler, Sawsan Youssef, Sindy Liao-Chan, Jacob Glanville, Natasha Christie-Holmes, Samira Mubareka, Scott D. Gray-Owen, John L. Rubinstein, Bebhinn Treanor, Jean-Philippe Julien. Multivalency transforms SARS-CoV-2 antibodies into ultrapotent neutralizers. Nat. Commun. 12 - 3661, 2021.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
T and B lymphocytes are effectors of adaptive immunity. Their dysregulation have dramatic health consequences, and can lead to autoimmunity and blood cancers. Recently, immune receptors involved in dictating the fate of B and T cells have expanded drastically. Once of these critical receptor/ligand immune pair is the inducible co-stimulator (ICOS) and its ligand ICOSL, which emerged as a novel T/B-cell co-signaling pathway. The multiple roles reported for this immune complex position ICOS/ICOSL at the center of attention for immunotherapy. Accordingly, several therapeutic antibodies targeting this immune complex are under clinical investigation. However, structure-function studies of ICOS/ICOSL interaction are critically lacking. This proposal aims to use integrative structural biology to provide molecular details into the function and targeting of the ICOS/ICOSL immune complex. These structural blueprints will contribute to the design of next-generation therapies against autoimmune diseases and cancer. This knowledge, will also serve as the basis to develop agonist antibodies that could act as adjuvants of B cell maturation for vaccine purposes. Therefore, this study will aim to apply fundamental mechanistic approaches to answer biomedical research questions and the outcome will result in advances to both molecular medicine and biology of disease.
Оригинален текст от CORDIS (на английски).
Участници
Връзки
Данни: CORDIS, © Европейски съюз