Studies on Infection and Immunity in Experimental Typhoid Fever

Abstract

A disease resembling human typhoid fever has been induced by feeding live cultures of Salmonella typhosa to young chimpanzees, thus confirming the classical reports of Grünbaum and of Metchnikoff and Besredka. Detailed clinical observations, results of stool and blood cultures, and serological studies have confirmed the impression that the disease produced in chimpanzees closely resembles the mild form of human typhoid fever frequently seen in childhood. Gross and histologic examination of intestines, mesenteric lymph nodes, liver, spleen, and other organs of orally infected chimpanzees has demonstrated that the pathological findings are essentially indistinguishable from those seen in mild typhoid fever in man. The clinical spectrum of disease seen in chimpanzees ranged from moderately severe illness, through transitory illness, to afebrile infection with or without bacteriemia (but invariably with an antibody response), occasionally leading to the development of persisting biliary infection and the carrier state. Thus the range of illness observed in chimpanzees resembled that seen in man, except that the severe and complicated forms of typhoid fever were not observed in the chimpanzee. A reason for this difference is proposed and discussed. In contrast to the limitations imposed upon the interpretation of human epidemiologic observations, it has been possible to demonstrate in the chimpanzee that clinical variation in disease pattern from animal to animal may occur despite the administration of the same dose of the same bacterial strain simultaneously to an entire group of animals under study; in other words, variation in clinical pattern is dependent on inherent, non-specific host factors as well as on dose, strain or preceding state of immunity. Variation in dose and in challenge strain of S. typhosa employed also appeared to have an effect upon the likelihood of producing febrile as against afebrile infection in chimpanzees. The dose required to produce clinical disease, even with the more virulent strain, was excessively large compared to what is believed to be the dose required to produce illness in man; the limitations of this assumption, and suggested explanations for the findings, are discussed. The production of the spectrum of typhoid fever in the chimpanzee has made possible the study of basic problems in this disease which are not amenable to definitive study through the use of prevailing laboratory techniques.

Host adapted serotypes of Salmonella enterica

“…Host-adapted serotypes (Table 1) typically cause systemic disease in a limited number of related species. For example, Typhi, Gallinarum and Abortusovis are almost exclusively associated with systemic disease in humans [7], fowl [8] and ovines [5] respectively. However, some host Nicotinic acid [17] adapted serotypes can also cause disease in more than one host species : Dublin and Choleraesuis, for example, are generally associated with severe systemic disease in cattle and pigs respectively but may also infrequently cause disease in other mammalian hosts including humans [9][10][11].…”

“…We have defined this serotype as host-restricted since it exhibits a very narrow host-range, limited to humans and chimpanzees [7]. As for the other serotypes described below, infection is characterized by predominance of septicaemic over intestinal symptoms.…”

Studies on Infection and Immunity in Experimental Typhoid Fever

“…The presence of Vi and O antigens in the challenge inocula was confirmed serologically, using rabbit anti-Vi serum produced against Paracolobactrum ballerup, and rabbit anti-O serum produced against S. typhosa O-901 (7).…”

“…The characteristics of this strain and its infectivity for chimpanzees are described in a previous publication (7).…”

“…Challenge Procedures.--The challenge method employed was the same as that used to infect the animals initially (7). A 5 hour veal infusion agar culture of S. typhosa Ty2 was harvested in saline and the chimpanzees challenged orally by feeding each a banana inoculated with the desired number of organisms.…”