52 A. GOTTSCHALK 



The fundamental discoveries demonstrating the presence of a specific 

 cellular receptor for influenza virus were made by Hirst and by Burnet and 

 co-workers. Hirst (1942a,b) observed that influenza virus at 4°C. was 

 firmly adsorbed to fowl red cells and remained so for 18 hours; by forming 

 bridges between the cells the virus effected hemagglutination. Raising the 

 temperature to 37°C. resulted in spontaneous elution of the virus from the 

 red cells; whereas the latter were rendered inagglutinable, the virus remained 

 functional. Hirst concluded from the results (1) that the virus attaches itself 

 to a receptor substance at the surface of the red cell, and (2) that, by virtue of 

 an enzyme embedded in the virus coat, the receptor is altered in such a way as 

 no longer to bind the original or any fresh influenza virus. Additional and 

 quite independent proof for the existence of a specific receptor substance as 

 binding site for the influenza virus was provided when Burnet and co-workers 

 (1946; Burnet and Stone, 1947) showed that an exo-enzyme, obtained from the 

 culture filtrate of Vibrio cholerae and referred to as receptor-destroying 

 enzyme (RDE), rendered erythrocytes inagglutinable. The similarity of the 

 point of attack on cellular receptors of the soluble vibrio enzyme and of the 

 influenza virus particle was proved in several ways. Red cells, pretreated by 

 one of the two agents, failed to adsorb the other one, and adsorption at 0°C. 

 of one agent onto the intact cells blocked the absorption of the other agent. 

 Moreover, erythrocytes were made agglutinable by normal human sera to 

 equivalent titers when treated with influenza virus and with RDE, respec- 

 tively (Stone, 1947). 



Red blood cells are not host cells for influenza virus propagation. However, 

 further research left little doubt that they are most suitable models for the 

 virus-host cell interrelationship. It was found that influenza virus is 

 adsorbed to and elutes spontaneously from the susceptible respiratory cells 

 of the excised and surviving ferret and mouse lungs (Hirst, 1943; Fazekas de 

 St. Groth, 1948a), and that pretreatment with RDE renders the respiratory 

 surface of the excised mouse lung unable to adsorb influenza virus (Fazekas 

 de St. Groth, 1948a). Perhaps the most spectacular demonstration of the 

 essential role played by the cellular receptor in the initiation of virus infection 

 was the experiment in which infection of the respiratory tract of the intact 

 mouse by inhaled influenza virus was prevented by pretreatment with RDE 

 (Stone, 1948). 



The problem of specific influenza virus receptors was greatly advanced when 

 a group of natural substances, apparently with a common feature, was shown 

 to inhibit virus hemagglutination. Francis (1947) observed that normal 

 human serum inhibited hemagglutination by influenza virus, provided the 

 virus was previously heated at 56°C. for 30 minutes. Subsequently, a variety 

 of mucoproteins and mucopolysaccharides, some of them prepared in a highly 

 purified state, was found to inhibit hemagglutination by indicator virus. 



