DEVELOPMENT AND VALIDATION OF A LISTERIA-MONOCYTOGENES HOST-RESISTANCE MODEL IN FEMALE FISCHER-344 RATS

The mouse has been used almost exclusively as the experimental animal for host resistance studies in the United States. Host resistance mode ls in mice have been validated and these types of studies are an integ ral part of the National Toxicology Program's (NTP) immunotoxicology t esting program. Given that the Fischer 344 rat is the animal of choice for the NTP's toxicology studies, it was desirable to develop host re sistance assays in this rat strain, eliminating the need to extrapolat e doses between mouse and rat models. These studies were aimed at the development and the validation of a host resistance model to Listeria monocytogenes, a gram-positive, facultative intracellular bacterium, i n the Fischer 344 rat. The results demonstrated that L. monocytogenes infection in the Fischer 344 rat produces a very similar disease with respect to onset and duration as in the mouse. Animals inoculated with rep to 3 x 10(5) viable colony forming units (CFU) of L. monocytogene s were capable of resisting overt disease when they had an intact immu ne system. Inoculation of animals with 5x10(5) cfu resulted in 50% mor tality (5/10). However pretreatment with cyclophosphamide (an immunosu ppressive agent) followed by administration of 5 x 10(5) L. monocytoge nes resulted in 100% mortality. Conversely, pretreatment with Coryneba cterium parvum (an immune-enhancing agent) followed by administration of 5 x 10(5) L. monocytogenes resulted in 100% survival of animals. Ov ert disease without recovery was manifested in vehicle-treated animals inoculated with 8 x 10(5) and 1 x 10(6) microorganism, while earlier deaths and 100% survival resulted after pretreatment with cyclophospha mide or C. parvum, respectively. These data support the use of the inb red Fischer 344 rat for host resistance assays.