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，似乎在其感染周期中利用alpha1-3GT基因、其酶途径或其产物gal-alpha1-3Gal。本研究探讨了α 1- 3gt基因及其产物gal- α 1- 3gal（存在于宿主细胞上）如何影响灵长类动物的病毒感染性。在哺乳动物中，只有猴（旧大陆猴和猿）不表达2800万年前就已失活的alpha1-3GT基因。如果可以确定这些病原体确实在其感染周期中使用该基因，其酶途径或其产物，那么这种基因失活的选择性优势就变得清晰起来。为了测试这种可能性，实验将探索病毒能够（或不能）利用基因或基因产物的机制。在平行小鼠和灵长类细胞系的体外实验中，基因修饰表达alpha1-3GT基因，将测试病毒的差异感染性。此外，基因修饰的小鼠系，一个表达alpha1-3GT基因，另一个基因“敲除”，将用于证实体外工作和测试发病机制。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位点或受体。这有助于理解免疫系统对感染的反应，具有生物医学意义。它还阐明了病毒毒力的变异，包括其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动物群落中新发疾病的威胁。了解哪些病毒可能对特定宿主最危险，对于做出明智的政策决定至关重要。本博士论文研究项目将有助于一名美籍西班牙裔女研究生的学术培训。这项研究将扩大她的能力，为不断发展的全球疾病生态学学科做出贡献。

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.