The non-pathogenic mycobacteria M. smegmatis and M. fortuitum induce rapid host cell apoptosis via a caspase-3 and TNF dependent pathway

Abstract

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, non-pathogenic 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 non-pathogenic 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 non-pathogenic 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.

Calcium and Superoxide-Mediated Pathways Converge to Induce Nitric Oxide-Dependent Apoptosis in Mycobacterium fortuitum-Infected Fish Macrophages

“…M . fortuitum -induced apoptosis of human and murine macrophages has been reported earlier [ 41 ]. Our study for the first time reports the induction of similar pathological consequences in fish suggesting the pro-apoptotic trait to be a conserved virulence factor of M .…”

Phagocytosis influences the intracellular survival of Mycobacterium smegmatis via the endoplasmic reticulum stress response

“…Mtb-infected macrophages undergo apoptosis and contribute to host immune defense against mycobacterial infection [ 5 , 6 ]. Apoptosis of M. smegmatis -infected macrophages is induced by activation of caspase-3 and tumor necrosis factor-alpha (TNF-α), and regulation of apoptosis is important for the control of M. smegmatis in the host [ 7 ]. Phosphor-myo-inositol-lipoarabinomannan (LAM) and uncapped (Ara-) LAM have been isolated from the cell walls of M. smegmatis and M. fortuitum , and these compounds induce apoptosis [ 7 ].…”

“…Apoptosis of M. smegmatis -infected macrophages is induced by activation of caspase-3 and tumor necrosis factor-alpha (TNF-α), and regulation of apoptosis is important for the control of M. smegmatis in the host [ 7 ]. Phosphor-myo-inositol-lipoarabinomannan (LAM) and uncapped (Ara-) LAM have been isolated from the cell walls of M. smegmatis and M. fortuitum , and these compounds induce apoptosis [ 7 ]. Macrophages are also important in the innate immune system, and are involved in pathogen recognition and phagocytosis, as well as the production of cytokines [ 4 , 8 ].…”

Controlling Extra- and Intramacrophagic Mycobacterium abscessus by Targeting Mycolic Acid Transport

“…However, despite the presence of lysosomal material in these social phagosomes, the bacteria did not appear damaged, suggesting that they rescued themselves from the phagolysosomes (de Chastellier et al, 2009 ). In line with these results, R variant-containing THP1 macrophages were more acidified than those infected with the S variant and were autophagic and apoptotic, traits resembling infection with an RGM (Bohsali et al, 2010 ).…”