Wüthrich Marcel, Brandhorst Tristan T, Sullivan Thomas D, Filutowicz Hanna, Sterkel Alana, Stewart Douglas, Li Mengyi, Lerksuthirat Tassanee, LeBert Vanessa, Shen Zu Ting, Ostroff Gary, Deepe George S, Hung Chiung Yu, Cole Garry, Walter Jennifer A, Jenkins Marc K, Klein Bruce
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
University of Massachusetts Medical School, Worcester, MA 01655, USA.
Cell Host Microbe. 2015 Apr 8;17(4):452-65. doi: 10.1016/j.chom.2015.02.009. Epub 2015 Mar 19.
Fungal infections remain a threat due to the lack of broad-spectrum fungal vaccines and protective antigens. Recent studies showed that attenuated Blastomyces dermatitidis confers protection via T cell recognition of an unknown but conserved antigen. Using transgenic CD4(+) T cells recognizing this antigen, we identify an amino acid determinant within the chaperone calnexin that is conserved across diverse fungal ascomycetes. Calnexin, typically an ER protein, also localizes to the surface of yeast, hyphae, and spores. T cell epitope mapping unveiled a 13-residue sequence conserved across Ascomycota. Infection with divergent ascomycetes, including dimorphic fungi, opportunistic molds, and the agent causing white nose syndrome in bats, induces expansion of calnexin-specific CD4(+) T cells. Vaccine delivery of calnexin in glucan particles induces fungal antigen-specific CD4(+) T cell expansion and resistance to lethal challenge with multiple fungal pathogens. Thus, the immunogenicity and conservation of calnexin make this fungal protein a promising vaccine target.
由于缺乏广谱真菌疫苗和保护性抗原，真菌感染仍然是一个威胁。最近的研究表明，减毒的皮炎芽生菌通过T细胞识别一种未知但保守的抗原赋予保护作用。利用识别该抗原的转基因CD4(+) T细胞，我们在伴侣蛋白钙连蛋白中鉴定出一个在不同子囊菌中保守的氨基酸决定簇。钙连蛋白通常是一种内质网蛋白，也定位于酵母、菌丝和孢子的表面。T细胞表位作图揭示了一个在子囊菌门中保守的13个残基的序列。感染包括双相真菌、机会性霉菌以及导致蝙蝠白鼻综合征的病原体在内的不同子囊菌，会诱导钙连蛋白特异性CD4(+) T细胞的扩增。在葡聚糖颗粒中递送钙连蛋白疫苗可诱导真菌抗原特异性CD4(+) T细胞扩增，并对多种真菌病原体的致死性攻击产生抗性。因此，钙连蛋白的免疫原性和保守性使其成为一个有前景的疫苗靶点。
