Studies on Infection and Immunity in Experimental Typhoid Fever

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.