242 F. FENNER AND J. CAIRNS 



in the different organs on the same day with each strain, but that the titer 

 rose more slowly and to a lower level in infections with the Hampstead strain. 

 No detailed investigations have been made with the even less virulent 

 Pittsburgh strain, but the virus certainly multiplies in the liver and spleen 

 after peripheral inoculation and produces a slight rash in some mice. 



2. Yelloiv Fever 



The pathogenesis of yellow fever has been studied in rhesus monkeys by 

 Theiler (1951). He found that, after intradermal inoculation of a moderately 

 virulent strain, no multiplication of virus could be demonstrated in the skin 

 but early multiplication occurred in the local lymph node. This was followed 

 by invasion of the blood stream and then multiplication throughout the 

 reticuloendothelial system (lymph nodes, spleen, and bone marrow) and, 

 finally, by a stage of multiplication in the parenchymal cells of the liver, in 

 the adrenal gland, kidney, and elsewhere. The attenuated 17D strain, on the 

 other hand, multiplied in the local lymph node, invaded the blood, and was 

 then found in the general lymphoid tissue and bone marrow, but to much 

 lower titers than was the case with more virulent strains. Further, only 

 occasionally was 17D found in the liver and then only in trace amounts. The 

 attenuated strain thus multiplied to a lower titer in all sites and usually 

 failed to infect the vital target site of virulent yellow fever virus, the liver. 

 Strains intermediate in virulence between the 17D and the highly virulent 

 Asibi strain showed intermediate levels of multiplication in the lymphoid and 

 reticuloendothelial tissues, and in the liver. 



A further effect of attenuation of yellow fever virus and other members of 

 this group of arthropod-borne encephalitides is to lower the efficiency of their 

 transmission by mosquitoes (Whitman, 1939; Hammon and Reeves, 1943). 

 In part this operates merely by the reduction in the titer of circulating virus 

 in infected animals, and in part by some specific inability of mosquitoes, even 

 when infected, to transmit the attenuated virus (Whitman, 1939). 



For viruses of this group, therefore, the stages comprising the whole sequence 

 of infection includes those taking place in the vector — namely, infection and 

 penetration of the gut wall, circulation in the hemolymph and localization in 

 the salivary glands, and finally multiplication in the salivary glands and 

 excretion in the saliva at the time of feeding. There are at least two instances 

 of transmission being blocked by failure of the virus to surmount one of the 

 barriers in the vector (Merrill and Tenbroeck, 1935; McLean, 1955). 



3. Poliomyelitis 



Poliomyelitis shows perhaps the most complex series of events between 

 initial infection and the final production of symptoms. Figure 1 is j)robably 

 an oversimplification, but it illustrates the existence of at least four stages — 



