Viral Attenuation and Adaptation to Multiple Hosts

Bull 9726902许多病毒感染几种宿主物种。然而，病毒如何适应多个宿主并扩展到新的宿主的过程尚不清楚。感染多个物种的病毒通常由单独适应某些宿主的毒株和适应其他宿主的其他毒株组成。将一种病毒引入一个新的宿主物种，可能会导致在该物种中无法传播的感染（例如，埃博拉病毒、汉塔病毒和狂犬病病毒在人类中的感染），或者可能导致毁灭性的流行病（人类感染艾滋病毒，斑海豹感染海豹鼠疫，狮子感染犬瘟热病毒）。长期以来，病毒学家一直在利用不同宿主之间的差异适应，通过从密切相关物种的病毒中为一个物种制造疫苗，或在另一个物种的培养细胞中培养病毒来减弱毒力。本研究将开发一个噬菌体系统来研究对一对宿主物种的适应性。对噬菌体phi X174的初步研究揭示了一种单侧适应：在一个宿主上的长时间生长会导致抑制另一个宿主生长的变化，但在另一个宿主上的生长不会产生相应的影响。这项工作将在广泛的长期和短期条件下探索这种宿主特异性适应，监测适应性和伴随适应的基因型变化。这项研究应该为病毒宿主特异性适应和衰减的更大领域建立一个框架。更一般地说，这项工作是一个适应遗传基础的实验系统，它提供了在其他系统中尚未实现的遗传和适应性分析的操纵和彻底性水平。

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.