The NOD-scid IL2rγnull Mouse Model Is Suitable for the Study of Osteoarticular Brucellosis and Vaccine Safety

Osteoarticular brucellosis is the most common complication in Brucella-infected humans regardless of age, sex, or immune status. The mechanism of bone destruction caused by Brucella species remained partially unknown due to the lack of a suitable animal model. Here, to study this complication, we explored the suitability of the use of the NOD-scid IL2r gamma(null) mouse to study osteoarticular brucellosis and examined the potential use of this strain to evaluate the safety of live attenuated vaccine candidates. Mice were inoculated intraperitoneally with a single dose of 1 x 10(4), 1 x 10(5), or 1 x 10(6) CFU of B. abortus S19 or the vaccine candidate B. abortus S19 Delta vjbR and monitored for the development of side effects, including osteoarticular disease, for 13 weeks. Decreased body temperature, weight loss, splenomegaly, and deformation of the tails were observed in mice inoculated with B. abortus S19 but not in those inoculated with S19 Delta vjbR. Histologically, all S19-inoculated mice had a severe dose-dependent inflammatory response in multiple organs. The inflammatory response at the tail was characterized by the recruitment of large numbers of neutrophils, macrophages, and osteoclasts with marked bone destruction. These lesions histologically resembled what is typically observed in Brucella-infected patients. In contrast, mice inoculated with B. abortus S19 Delta vjbR did not show significant bone changes. Immunofluorescence, in situ hybridization, and confocal imaging demonstrated the presence of Brucella at the sites of inflammation, both intra-and extracellularly, and large numbers of bacteria were observed within mature osteoclasts. These results demonstrate the potential use of the NOD-scid IL2r gamma(null) mouse model to evaluate vaccine safety and further study osteoarticular brucellosis.