Genetically determined disparate innate and adaptive cell-mediated immune responses to pulmonary Mycobacterium bovis BCG infection in C57BL/6 and BALB/c mice

The current study was designed to investigate the impact of genetic heterog eneity on host immune responses to pulmonary intracellular infection by usi ng two mouse strains of distinct genetic background, C57BL/6 and BALB/c mic e, and a model intracellular pathogen, Mycobacterium bovis BCG. Upon infect ion, compared to C57BL/6 mice, BALB/c mice developed an earlier response of interleukin 12 (IL-12), gamma interferon (IFN-gamma), tumor necrosis facto r alpha, and macrophage chemoattractive protein 1, and greater neutrophilic influx to the lung by days 7 and 14. However, the level of these cytokines at days 27, 43, and 71 was much lower in BALB/c mice than in C57BL/6 mice. The magnitude of cellular responses was also much lower in the lung of BAL B/c mice around day 27. Histologically, while C57BL/6 mice developed lympho cytic granulomas, BALB/c mice displayed atypical granulomas in the lung, Of importance, the level of type 2 cytokines IL-4 and IL-10 remained low and similar in the lung of both C57BL/6 and BALB/c mice throughout. Furthermore , lymphocytes isolated from systemic and local lymphoid tissues of infected BALB/c mice demonstrated a markedly lower antigen-specific IFN-gamma recal l response. While the number of mycobacterial bacilli recovered from both t he lung and spleen bf BALB/c mice was similar to that in C57BL/6 mice at da y 14, it was higher than that in C57BL/6 mice at day 43. However, it was ev entually leveled off to that in C57BL/6 counterparts later. These results s uggest the following: (i) genetic heterogeneity can lead to differential in nate and adaptive cell-mediated immune responses to primary pulmonary mycob acterial infection; (ii) it is the level of adaptive, but not innate, immun e response that is critical to host resistance; and (iii) a lower type 1 im mune response in BALB/c mice is not accompanied by a heightened type 2 resp onse during pulmonary mycobacterial infection.