Viral Attenuation and Adaptation to Multiple Hosts

公牛9726902许多病毒感染几个寄主物种。然而，病毒适应多个宿主以及扩展到新宿主的过程尚不清楚。感染多个物种的病毒通常由分别适应某些宿主的毒株和适应其他宿主的其他毒株组成。将病毒引入新的宿主物种可能会导致在该物种中没有传播的感染(例如，人感染埃博拉病毒、汉塔病毒和狂犬病病毒)，或者可能导致毁灭性的流行病(人类感染艾滋病毒、海豹的海豹鼠疫、狮子的犬瘟热病毒)。长期以来，病毒学家一直在利用替代宿主之间的差异适应，要么利用密切相关物种的病毒为一种物种创造疫苗，要么通过在另一物种的培养细胞中培养病毒来减弱毒力。这项研究将开发一个噬菌体系统来研究对一对寄主物种的适应。对噬菌体Phi x174的初步研究揭示了一种单方面的适应：在其中一种宿主上长期生长会导致变化，抑制另一种宿主的生长，但在另一种宿主上的生长不会产生相应的影响。拟议的工作将在广泛的长期和短期条件下探索这种宿主特有的适应，监测伴随适应而来的适应性和基因变化。这项研究应该为更大范围的宿主特异性适应和病毒衰减建立一个框架。更广泛地说，这项工作是一个适应的遗传基础的实验系统，提供了在其他系统中没有达到的遗传和适应性分析的操作水平和彻底性。

Bull 9726902 Many viruses infect several host species. Yet the process by which a virus adapts to multiple hosts as well as expands to new hosts is not known. Viruses that infect multiple species often consist of strains that are individually adapted to some hosts, with other strains adapted to other hosts. Introduction of a virus into a new host species may result in infections that are not propagated in that species (e.g., human infections by Ebola, hanta, and rabies virus) or may cause devastating epidemics (HIV in humans, seal plague in harbor seals, canine distemper virus in lions). Virologists have long exploited differential adaptation among alternative hosts by creating vaccines for one species either from viruses of a closely-related species or by growing viruses in cultured cells of another species to attenuate virulence. This study will develop a bacteriophage system to study adaptation to a pair of host species. Preliminary work with the phage phi X174 has revealed a one-sided adaptation: prolonged growth on one of the hosts results in changes that inhibit growth on the other host, but growth on the other host does not have the corresponding effect. The proposed work will explore this host-specific adaptation under a wide range of long term and short term conditions, monitoring fitness and genotype changes that accompany the adaptation. The study should establish a framework for the larger realm of host-specific adaptation and attenuation in viruses. More generally, the work is an experimental system of the genetic basis of adaptation that offers a level of manipulation and thoroughness of genetic and fitness assay that has not been achieved in other systems.