Determinants of natural immunity against tuberculosis in an endemic setting:: factors operating at the level of macrophage-Mycobacterium tuberculosis interaction

We aimed to delineate factors operating at the interface of macrophage-mycobacterium interaction which could determine the fate of a 'subclinical' infection in healthy people of a tuberculosis-endemic region. Ten study subjects (blood donors) were classified as 'high' or 'low' responders based on the ability of their monocyte-derived macrophages to restrict or promote an infection with Mycobacterium tuberculosis. Bacterial multiplication between days 4 and 8 in high responder macrophages was significantly lower (P < 0.02) than low responders. All donor sera were positive for antibodies against cell-membrane antigens of M. tuberculosis and bacilli opsonized with heat-inactivated sera were coated with IgG. In low responder macrophages, multiplication of opsonized bacilli was significantly less (P < 0.04) than that of unopsonized bacilli. The levels of tumour necrosis factor (TNF)-alpha and interleukin (IL)-12 produced by infected high responder macrophages was significantly higher (P < 0.05) than low responders. However, infection with opsonized bacilli enhanced the production of IL-12 in low responders to its level in high responders. The antibody level against membrane antigens was also significantly higher (P < 0.05) in high responders, although the antigens recognized by two categories of sera were not remarkably different. Production of certain other cytokines (IL-1 beta, IL-4, IL-6 and IL-10) or reactive oxygen species (H2O2 and NO) by macrophages of high and low responders did not differ significantly. The study highlights the heterogeneity of Indian subjects with respect to their capability in handling subclinical infection with M. tuberculosis and the prominent role that TNF-alpha, opsonizing antibodies and, to a certain extent, IL-12 may play in containing it.