Wang Huafeng, Lee Taek-Jin, Fites Scott J, Merkhofer Richard, Zarnowski Robert, Brandhorst Tristan, Galles Kevin, Klein Bruce, Wüthrich Marcel
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, United States of America.
Department of Medicine (Infectious Disease Division), University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, United States of America.
PLoS Pathog. 2017 Aug 9;13(8):e1006568. doi: 10.1371/journal.ppat.1006568. eCollection 2017 Aug.
The development of vaccines against fungi and other intracellular microbes is impeded in part by a lack of suitable adjuvants. While most current vaccines against infectious diseases preferentially induce production of antibodies, cellular immunity is essential for the resolution of fungal infections. Microbes such as fungi and Mycobacterium tuberculosis require Th17 and Th1 cells for resistance, and engage the C-type lectin receptors including Dectin-2. Herein, we discovered a novel Dectin-2 ligand, the glycoprotein Blastomyces Eng2 (Bl-Eng2). Bl-Eng2 triggers robust signaling in Dectin-2 reporter cells and induces IL-6 in human PBMC and BMDC from wild type but not Dectin-2-/- and Card9-/- mice. The addition of Bl-Eng2 to a pan-fungal subunit vaccine primed large numbers of Ag-specific Th17 and Th1 cells, augmented activation and killing of fungi by myeloid effector cells, and protected mice from lethal fungal challenge, revealing Bl-Eng2's potency as a vaccine adjuvant. Thus, ligation of Dectin-2 by Bl-Eng-2 could be harnessed as a novel adjuvant strategy to protect against infectious diseases requiring cellular immunity.
针对真菌和其他细胞内微生物的疫苗开发在一定程度上受到缺乏合适佐剂的阻碍。虽然目前大多数针对传染病的疫苗优先诱导抗体产生，但细胞免疫对于解决真菌感染至关重要。诸如真菌和结核分枝杆菌等微生物需要Th17和Th1细胞来产生抵抗力，并激活包括Dectin-2在内的C型凝集素受体。在此，我们发现了一种新型的Dectin-2配体，即糖蛋白芽生菌Eng2（Bl-Eng2）。Bl-Eng2在Dectin-2报告细胞中引发强烈的信号传导，并在野生型小鼠而非Dectin-2基因敲除小鼠和Card9基因敲除小鼠的人外周血单个核细胞和骨髓来源的树突状细胞中诱导白细胞介素-6的产生。将Bl-Eng2添加到一种泛真菌亚单位疫苗中，可引发大量抗原特异性Th17和Th1细胞，增强髓样效应细胞对真菌的激活和杀伤作用，并保护小鼠免受致命的真菌攻击，这揭示了Bl-Eng2作为疫苗佐剂的效力。因此，Bl-Eng-2与Dectin-2的结合可作为一种新型佐剂策略，用于预防需要细胞免疫的传染病。
