Background: The HIV pandemic raised the potential for facultative-pathogenic mycobacterial species like,
Mycobacterium kansasii, to cause disseminating disease in humans with immune deficiencies. In contrast, nonpathogenic mycobacterial species, like M. smegmatis, are not known to cause disseminating disease even in
immunocompromised individuals. We hypothesized that this difference in phenotype could be explained by the
strong induction of an innate immune response by the non-pathogenic mycobacterial species.
Results: A comparison of two rapid-growing, non-pathogenic species (M. smegmatis and M. fortuitum) with two
facultative-pathogenic species (M. kansasii and M. bovis BCG) demonstrated that only the non-pathogenic bacteria
induced strong apoptosis in human THP-1 cells and murine bone marrow-derived macrophages (BMDM) and
dendritic cells (BMDD). The phospho-myo-inositol modification of lipoarabinomannan (PI-LAM) isolated from nonpathogenic species may be one of the cell wall components responsible for the pro-inflammatory activity of the
whole bacteria. Indeed, PI-LAM induces high levels of apoptosis and IL-12 expression compared to the mannosyl
modification of LAM isolated from facultative-pathogenic mycobacteria. The apoptosis induced by non-pathogenic
M. smegmatis was dependent upon caspase-3 activation and TNF secretion. Consistently, BALB/c BMDM responded
by secreting large amounts of TNF upon infection with non-pathogenic but not facultative-pathogenic
mycobacteria. Interestingly, C57Bl/6 BMDM do not undergo apoptosis upon infection with non-pathogenic
mycobacteria despite the fact that they still induce an increase in TNF secretion. This suggests that the host cell
signaling pathways are different between these two mouse genotypes and that TNF is necessary but not sufficient
to induce host cell apoptosis.
Conclusion: These results demonstrate a much stronger induction of the innate immune response by nonpathogenic versus facultative-pathogenic mycobacteria as measured by host cell apoptosis, IL-12 and TNF cytokine
induction. These observations lend support to the hypothesis that the strong induction of the innate immune
response is a major reason for the lack of pathogenicity in fast-growing mycobacteria.