Granuloma formation is required to contain bacillus growth and delay mortality in mice chronically infected with Mycobacterium tuberculosis

Previous studies in this laboratory have shown that mice with a gene disrup tion to the intracellular adhesion molecule-1 (ICAM-K/O) express normal cel l-mediated immunity but cannot mount delayed-type hypersensitivity reaction s following;Mycobacterium tuberculosis infection. However, even in the abse nce of any appreciable granuloma formation, these mice control bacterial gr owth for at least 90 days. While not required to control the infection init ially, we hypothesized that granuloma formation was required to control chr onic infection, acting by surrounding infected cells to prevent bacterial d issemination. To test this, ICAM-1 knockout mice were infected with a tow d ose aerosol of M. tuberculosis Erdman and were found to succumb to infectio n 136 +/- 30 days later, displaying highly elevated bacterial loads compare d to wild-type mice. Lung tissue from ICAM-K/O mice displayed extensive cel lular infiltration and widespread tissue necrosis, but no organized granulo matous lesions were evident, whereas the control mice displayed organized c ompact granulomas. These data demonstrate that while a granulomatous respon se is not required initially to control M. tuberculosis infection, absence of granulomas during chronic infection leads to increased bacterial growth and host death. Thus these data support the hypothesis that granuloma forma tion is required to control chronic infection, acting by surrounding and wa lling off sites of infection to prevent bacterial dissemination and maintai n a state of chronic infection.