The Diversion of Macromolecular Synthesis in L-Cells Towards Ends Dictated by Mengovirus (2025)

The last few years have seen the beginnings of biochemical and physiological studies on animal virus multiplication. Work of this kind with bacterial viruses had begun in the early 1950's and provided much information before research on animal viruses was initiated. The delay in the study of animal systems was due to the great difficulties which attended the development of methods of cell culture and of quantitative virology. The solution of these problems, through the painstaking work of T. Puck, H. Eagle, R. Dulbecco and their associates, has made possible the recent rapid advance in our knowledge of the rare intimate details of cell and virus growth (cf. volume 27 of the Cold Spring Harbor Symposium on Quantitative Biology). The techniques which were developed during the study of bacteria and bacteriophages and the large body of data and theory which was accumulated, have contributed greatly to the rapidity with which our understanding of mammalian systems has increased over the last few years. In the case of the details of viral nucleic acid metabolism, the pioneering work of S.S. Cohen and A. Kornberg and the many studies which followed on bacterial viruses have provided much knowledge about the enzymes involved in bacteriophage multiplication and the physiological changes wrought in bacteria by infection (Cohen, 1961; Kornberg, 1961). In attempting to provide comparable information about mammalian viruses, we must of necessity follow their footsteps. The following presentation is divided into four main sections. The first is an Introduction which provides some necessary and some incidental background to the experiraental sections. The discovery of Mengovirus and its characterization are covered in order to place the biochemical evidence in a framework of historical continuity. This discussion is by no means complete but is meant to be sufficient to provide some understanding of the place of this virus relative to some of its closest relatives, especially poliovirus. The introduction then goes on to discuss at some length the structure of the virus and its multiplication in two different cell types. Finally, the literature on the time course of virus precursor synthesis is reviewed. It was deemed advisable to separate the experimental work into two sections since there are two quite different topics under examination. The first experimental section deals with studies on the Mengovirus-induced inhibition of cellular RNA synthesis. The inhibition is shown to be due to inactivation of the DNA-enzyme complex responsible for cellular RNA synthesis. In the second experimental section, evidence is presented concerning the enzymatic mechanism of the synthesis of viral RNA. The results indicate that virus infection causes the production of a new, cytoplasmic RNA polymerase with properties which are consistent with its being the enzyme responsible for viral RNA synthesis. Each experimental section has its own introduction where relevant problems are discussed. The fourth major division of the thesis integrates the conclusions of the three earlier sections into a general model of the multiplication of Mengovirus and related viruses. In this final discussion, certain aspects of virus multiplication are discussed which were not dealt with earlier and some very recent experiments are mentioned.