Yilmaz Bahtiyar, Portugal Silvia, Tran Tuan M, Gozzelino Raffaella, Ramos Susana, Gomes Joana, Regalado Ana, Cowan Peter J, d'Apice Anthony J F, Chong Anita S, Doumbo Ogobara K, Traore Boubacar, Crompton Peter D, Silveira Henrique, Soares Miguel P
Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6, 2780-156 Oeiras, Portugal.
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook II, Room 125, 12441 Parklawn Drive, Rockville, MD 20852-8180, USA.
Cell. 2014 Dec 4;159(6):1277-89. doi: 10.1016/j.cell.2014.10.053.
Glycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the UDP-galactose:β-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galβ1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.
糖基化过程处于高度的自然选择压力之下，大概是因为这些过程能够调节对感染的抵抗力。在这里，我们研究了尿苷二磷酸半乳糖：β-半乳糖苷-α1-3-半乳糖基转移酶（α1,3GT）基因的失活是否能提供针对疟原虫感染的保护作用。该基因的失活消除了Galα1-3Galβ1-4GlcNAc-R（α-半乳糖）聚糖的表达，并使得人类能够产生抗α-半乳糖抗体（Abs）。疟原虫是疟疾的病原体，也是人类进化的主要驱动力。我们证明，疟原虫和人类肠道致病共生菌大肠杆菌O86:B7都表达α-半乳糖，并且抗α-半乳糖抗体与人类以及α1,3GT缺陷小鼠抵抗疟疾传播的保护作用相关。当被大肠杆菌O86:B7定殖时，α1,3GT缺陷小鼠会产生保护性抗α-半乳糖抗体。接种疟蚊后，抗α-半乳糖抗体立即在皮肤中靶向疟原虫子孢子，介导补体介导的细胞毒性作用。针对α-半乳糖的疫苗接种可使小鼠获得针对疟疾的无菌保护，这表明类似的方法可能会减少人类疟疾的传播。
