VARIATION IN VIRULENCE 241 



Generalizing very broadly from this model, it can be said that in such virus 

 infections several steps must occur in sequence: (1) Initial multiplication at 

 the site of entry — this may eventually produce an apparent lesion, like the 

 primary lesion in mousepox, or it may be inapparent. Sometimes multiplica- 

 tion of this type on a mucous surface (respiratory tract or gut) may produce 

 free virus which can infect others. (2) At an interval after implantation, 

 which may be short or not, virus enters the lymphatics. The local lymph node 

 acts as a barrier to further spread, and a further process of virus multiplica- 

 tion must occur in the lymph node if the infection is to become generalized. 

 (3) Once the lymph node barrier is surmounted, the virus has immediate 

 access to the blood stream, and a wide variety of different sites of multiplica- 

 tion is available. Important among these are the vascular endothelial cells 

 and the scavenger cells of the reticuloendothelial system (in the spleen, bone 

 marrow, lymph nodes, and liver). The low entry rate of virus into the blood 

 stream during this primary viremia, and the abundance of cells susceptible to 

 infection ensure that little free virus can be recovered from the blood at this 

 stage. (4) Progressive multiplication in the cells just entered, perhaps with 

 further distribution of virus via the circulation, leads eventually to frank 

 viremia. By the time this stage is reached changes have occurred in the host 

 reaction due to antibody production (both sensitization, in its broadest sense 

 and serum antibodies being involved). (5) This combination of factors ushers 

 in the next stage of the disease, i.e., localization and multiplication at the 

 "secondary" sites (skin, brain, etc.) leading to the various typical syndromes 

 of the generalized infection. Especially in the case of the central nervous 

 system, there are barriers which may prevent this final step, perhaps in the 

 vast majority of cases of infection. 



Such a definite series of obligatory steps , each involving different types of cells, 

 allows ample scope for different final results (i.e., different degrees of virulence) 

 to be due to any combination of a number of variations in virus or host. Some 

 virus strains may be a virulent because they merely have a low ability to multiply 

 in the various tissues involved; others may be defective at some particular 

 point in the sequence. The following examples of virus infections in systems 

 involving sequence provide several instances of both types of defect. 



1. Mousepox 



Some of the less virulent variants of viruses which cause severe generalized 

 diseases go through exactly the same sequence of events as the virulent 

 strains, and are not "blocked" at any stage of the sequence. This is true of 

 two attenuated strains of ectromelia virus, the "Hampstead egg" strain 

 (Fenner, 1948b), and a strain passaged in tissue culture by Dr. G. Ruckle 

 (Pittsburgh strain). Comparison of the growth of Moscow and Hampstead 

 egg strain in various organs (Fenner, 1948b) showed that virus was detected 

 vol. in — 16 



