Progressive and fatal infection with attenuated Mycobacterium bovis (BCG) in nude mice

Congenitally athymic nude mice (nu/nu) were infected intravenously with Mycobacterium bovis BCG Japanese strain under specified pathogen-free (SPF) or germ-free (GF) conditions. SPF euthymic litter mates (nu/+) serving as controls were found to tolerate the infection well, while SPF nu/nu mice following infection of 3 X 10(7) organisms died by week-36. Animals having received a very small dose (3 X 10(0) of organisms and their non-infected cage mates showed no evidence of infection at week 37 post-infection. Time-course observations carried out on SPF and GF nu/nu mice following infection with 10(5) or 10(6) organisms revealed that the number of organisms in the liver and spleen reached 10(6) to 10(7) viable units per organ at week 12 and this level was maintained for 50 weeks post-infection. Bacillary counts in the kidney and lung increased progressively and reached a level of 10(7) to 10(8) at the terminal stage of infection. In the liver, spleen and lymph nodes of nu/nu mice, granulomas were noted 12 weeks postinfection. The granulomas were composed of macrophages and accompanied by slight infiltration of lymphocytes, plasma cells and a small number of polymorphonuclear leucocytes. In later infection stages, small aggregations of pigmented macrophages packed with acid-fast bacilli were present in the liver, spleen and lymph nodes. Lesions with large foci of bacilli-laden macrophages developed progressively in the kidney, lung and subcutaneous and periosteal connective tissues. Periosteal granulomatous lesions, sometimes accompanied by exudation, intruded occasionally into the bone marrow, resulting in extensive granulomatous osteomyelities.