PATHOGENICITY AND TOXIN PRODUCTION 591 



The studies of Dick and Dick (1924a, b, 1925a, b) on the aetiology of scarlet fever, and 

 the observations of subsequent workers, have shown that Str. pyogenes produces another 

 filtrable toxin, which is quite distinct from the hsemolysin and leucocidin. The properties 

 of this toxin are described in some detaU in Chapter 66. For our immediate purpose 

 a brief summary will suffice. 



The injection of this toxin in small amounts into the skin of persons susceptible to its 

 action gives rise to a characteristic locaUzed erythema. Its injection in larger amounts 

 in particularly susceptible persons may result in a generalized erythematous rash, associated 

 with fever and malaise (" miniature scarlet fever "). Because of this action in man this 

 component of streptococcal filtrates is known as the erythrogenic toxin, or scarlatinal toxin. 

 It is toxic for the rabbit when injected intravenously, but its minimal lethal dose is very 

 large (5-10 ml. of an unconcentrated filtrate). It can be concentrated and partially purified 

 by various methods (Hartley 1928, Pulvertaft 1928), but the M.L.D. remains relatively 

 large (0-1-1 ml.), and the purification is certainly very incomplete. A skin reaction has 

 been induced in certain laboratory animals, but none of them is as sensitive as man, and 

 many are quite resistant. 



The erythrogenic toxin differs sharply from streptococcal hsemolysin in being relatively 

 heat resistant. It requires a temperature of 96° C. for 45 minutes for complete inactivation. 

 It is antigenic, producing an antitoxin that gives specific neutralization, and is immunologic- 

 ally distinct from antistreptolysin (Todd, Lambent and Hill 1933). The concentrated 

 toxiii can be titrated by the flocculation method, using specific antitoxin (Rane and 

 Wyman 1937, Hottle and Pappenheimer 1941). 



This does not exhaust the toxic armoury of Str. pyogenes. It has been shown (Tillett 

 and Garner 1933) that pathogenic strains of haemolytic streptococci produce a substance 

 that dissolves human fibrin (see also Tillett, Edwards and Garner 1934, TiUett 1935). This 

 fibrinolysin seems to be almost constantly present in strains of Group A haemolytic strepto- 

 cocci (Lancefield and Hare 1935, Hare 1935, Hare and Maxted 1935, Colebrook, Maxted 

 and Johns 1935), and is formed by the matt-colony-producing strains of Groups C and G. 

 The action appears to be relatively specific for the fibrin of certain animal species. Thus 

 the fibrinolysin produced by many strains of Str. pyogenes dissolves human, but not 

 rabbit fibrin. The fibrinolysin also acts on human fibrinogen, so altering it that it is 

 no longer able to form fibrin. Garner and TiUett (1934) have been able to obtain partially 

 purified streptococcal fibrinolysin from filtrates by alcohol precipitation, followed by 

 adsorption and elution. The product obtained is remarkably heat resistant ; its activity 

 may be maintained after heating at 100° C. for 50 minutes. It exerts no hydrolytic 

 action on casein, gelatin or peptone. Its lytic action on human fibrin appears to be 

 associated with a slight increase in the amino-nitrogen content of the reacting mixture. 



Finally, Duran-Reynals (1933) has described the presence in lysates and filtrates of 

 invasive streptococci of a spreading factor, which markedly increases the permeabihty 

 of the rabbit's skin to suspensions of Indian ink, or to bacterial cells. A similar substance 

 has been extracted by Chain and Duthie (1939) from the testicle, and has been shown 

 to hydrolyse the muco polysaccharide, hyaluromc acid, found by Meyer and Palmer (1936) 

 in vitreous humour and the umbihcal cord, and by Kendall, Heidelberger and Dawson 

 (1937) in the capsular substance of Group A streptococci. The enzyme hyaluronidase 

 appears to be identical with the spreading factor. What part this enzyme plays in favour- 

 ing the invasion of the tissues by streptococci, or what part the hyaluronic acid in the 

 capsular substance plays in protecting the organisms from the cells or antibodies in the 

 tissues of the host is still subject to discussion. According to McClean (1941) the develop- 

 ment of capsules and hyaluronidase formation appear to be mutually exclusive. Seastone 

 (1943) observed that haemolytic streptococci from severe infections had a higher average 

 muco-polysaccharide content than those from mild infections, suggesting that capsular 

 material was favourable to the organism, but a relation between cajisule formation and 

 virulence has still got to be proved. Hirst (1941), for example, found that decapsulation 

 of the organisms with leech extract protected guinea-pigs and mice from fatal infection 



