VARIATION IN VIRULENCE 235 



Even in simple systems, the spread of infection is occasionally seen to be 

 limited. Thus, varicella virus infection spreads among cells in tissue culture 

 only by direct contact between cells and serial passage can be effected only 

 with ground-up cells, not with the fluid supernatant (Weller, 1953). 



Apart from those numerous instance (dealt with in the next section) where 

 the natural course of infection demands the surmounting of successive 

 barriers, there is ample evidence that the existence of an ordered organization 

 of the host cells into a tissue may impose certain limitations upon the spread 

 of infection. Thus, increasing the area involved by the inoculum by adding 

 hyaluronidase, increases both the infectivity and the size of the resulting 

 lesions of vaccinia virus in the rabbit skin, as well as increasing the proba- 

 bility of subsequent generalized infection (Duran-Reynals, 1929, 1933; 

 Sprunt, 1941); this effect of hyaluronidase is seen also with herpes and 

 vesicular stomatitis infection of rabbit skin (Hoffman, 1931). An enhanced 

 response was found with Borna disease infection of rabbit brain (Hoffman, 

 1931), and with herpes infection of mouse brain (Levaditi et at., 1949). 

 Presumably in these infections the spread of virus from cell to cell is limited 

 under normal conditions. Since, in the same tissues, hyaluronidase had no 

 discernible effect upon the progression of infection by rabies, St. Louis 

 encephalitis, or Lansing poliovirus, the infection produced by these viruses 

 does not suffer the same limitations (Levaditi et ah, 1949). 



Perhaps paralleling these observations are those examples in which the 

 severity of a virus infection is increased by the presence of nonspecific 

 irritants (Jones, 1950; Findlay and Howard, 1950a) or by coexistent infec- 

 tion by some quite unrelated virus (Lepine and Marcenac, 1948; Findlay and 

 Howard, 1950b). 



All examples of the production of localized lesions, whether in a two- 

 dimensional structure, such as the monolayer overlaid by agar (Dulbecco, 

 1952), or a three-dimensional structure, such as the liver (Marchal, 1930), 

 provide evidence for limitation of spread — spread either of the infecting 

 virus particles or, in the case of the neoplastic viruses, of the primarily infected 

 cells (Keogh, 1938). Histological studies have provided evidence for the 

 slowness of spread of certain virus infections in the nervous system where 

 others spread rapidly, and this has been demonstrated also by direct assay of 

 the virus content of various parts of brain (Webster and Fite, 1934; Sabin and 

 Olitsky, 1937; King, 1939). 



Unfortunately, although this subject of the spread of virus infection 

 through organized systems of cells may loom large in the future when know- 

 ledge of virus infection in simple systems has to be applied to complex hosts, 

 available information at the moment amounts merely to demonstrating that 

 the subject exists. Despite this lack, we shall now discuss certain examples of 

 the variation of viruses infecting complex tissues under their own separate 



