Aerosol infection of mice with recombinant BCG secreting murine IFN-gamma partially reconstitutes local protective immunity

To better understand the contribution of interferon-gamma (IFN-gamma) to th e immune response during the first 60 days of mycobacterial infection in th e lungs, IFN-gamma gene disrupted (IFN-gamma-/-) mice were infected via aer osol with recombinant Mycobacterium bovis Bacillus Calmette-Guerin (BCG) se creting murine IFN-gamma (BCG-IFN-gamma) and compared to mice infected with recombinant BCG containing the vector only (BCG-vector). When IFN-gamma-/- mice were infected with BCG-vector, increasing bacillary loads and large u ndifferentiated granulomas that did not express inducible nitric oxide synt hase (iNOS) were observed in the lungs. In contrast, infection with BCG-IFN -gamma resulted in reduced bacillary load and better differentiated granulo mas containing epithelioid macrophages expressing iNOS as well as reduced l evels of interleukin 10 (IL-10) mRNA. However, local production of IFN-gamm a by the recombinant BCG did not protect IFN-gamma-/- mice from subsequent challenge with M. tuberculosis. Infection of IFN-gamma-/- peritoneal macrop hages in vitro with BCG-IFN-gamma led to induction of iNOS expression and l ower IL-10 mRNA levels. Nevertheless, the growth of the intracellular BCG w as unaffected. Since IFN-gamma induced-iNOS protein and reduced IL-10 produ ction were insufficient to control mycobacterial growth in vitro, the resul ts suggest that additional mediator(s) present in vivo are required for con trol of mycobacterial growth. (C) 2000 Academic Press.