Doctoral Dissertation Improvement Grant: Gene Loss During Catarrhine Evolution With Possible Implications for the Evolution of Resistance to Viral Infections

某些病原体，包括病毒，似乎在它们的感染周期中利用Alpha1-3GT基因、其酶途径或其产物Gal-Alpha1-3Gal。这项研究调查了Alpha1-3GT基因及其产物Gal-Alpha1-3Gal(存在于宿主细胞中)如何影响灵长类动物的病毒感染性。在哺乳动物中，卡他猴(东半球猴子和猿类)是唯一不表达α1-3GT基因的动物，该基因在约2800万年前被灭活。如果可以确定这些病原体确实在它们的感染周期中使用该基因、其酶途径或其产物，那么该基因失活的选择性优势就变得显而易见了。为了测试这种可能性，实验将探索病毒可以(或不能)利用基因或基因产物的机制。在平行的小鼠和灵长类细胞系上进行的体外实验将测试病毒的不同传染性。此外，一种表达alpha1-3GT基因的转基因小鼠品系和另一种表达alpha1-3gt基因的转基因小鼠品系将被用于证实体外工作和测试致病机理。这项研究阐明了不同的病毒如何使用糖基化途径或碳水化合物作为结合部位或受体。这有助于了解免疫系统如何对感染做出反应，从而具有生物医学意义。它还阐明了卡他犀类和其他物种中病毒毒力的差异，包括它对选择压力和物种生存的贡献。这项研究的更广泛影响包括灵长类动物保护，因为保护生物学家越来越意识到灵长类群落中新出现的疾病的威胁。了解哪些病毒可能对特定主机最危险，这对于做出明智的策略决策可能是至关重要的。这项博士论文研究项目将有助于对一名作为美国拉美裔社区成员的女性研究生的学术培训。这项研究将扩大她为全球疾病生态学日益增长的学科做出贡献的能力。

Certain pathogens, including viruses, appear to utilize the alpha1-3GT gene, its enzymatic pathway, or its product gal-alpha1-3Gal in their infection cycles. This study investigates how the alpha1-3GT gene and its product, gal-alpha1-3Gal (present on host cells), affect viral infectivity in primates. Among mammals, catarrhines (Old World monkeys and apes) are the only ones that do not express the alpha1-3GT gene which was inactivated ~28 million years ago. If it can be established that these pathogens do indeed use the gene, its enzymatic pathway, or its product, in their infection cycles, then the selective advantage of this gene inactivation becomes clear. To test this possibility, experiments will probe the mechanisms by which viruses can (or cannot) utilize the gene or gene product. In vitro experiments on parallel mouse and primate cell lines, genetically modified to express the alpha1-3GT gene, will test the differential infectivity of viruses. Additionally, genetically modified mouse lines, one expressing the alpha1-3GT gene and the other with the gene "knockedout" will be used to corroborate in vitro work and to test pathogenesis.This research elucidates how different viruses use glycosylation pathways or carbohydrates as binding sites or receptors. This has biomedical implications by contributing to understanding how the immune system responses to infection. It also elucidates variation in viral virulence in catarrhines and other species including its contribution to selective pressures and species survival. The broader impacts of this study include primate conservation, as conservation biologists are increasingly aware of the threat of emerging diseases in primate communities. Understanding which viruses are likely to be most dangerous to particular hosts may be critical in making informed policy decisions. This doctoral dissertation research project will contribute to the academic training of a female graduate student who is a member of the American Hispanic community. This research will broaden her ability to contribute to the growing discipline of global disease ecology.