Mycobacterium leprae induces insulin-like growth factor and promotes survival of Schwann cells upon serum withdrawal.

Peripheral nerve lesions are considered the most relevant symptoms of leprosy, a chronic infectious disease caused by Mycobacterium leprae. The strategies employed by M. leprae to infect and multiply inside Schwann cells (SCs), however, remain poorly understood. In this study, it is shown that treatment of SCs with M. leprae significantly decreased cell death induced by serum deprivation. Not displayed by Mycobacterium smegmatis or Mycobacterium bovis BCG, the M. leprae survival effect was both dose dependent and specific. The conditioned medium (CM) of M. leprae-treated cultures was seen to mimic the protective effect of the bacteria, suggesting that soluble factors secreted by SCs in response to M. leprae were involved in cell survival. Indeed, by quantitative RT-PCR and dot blot/ELISA, it was demonstrated that M. leprae induced the expression and secretion of the SC survival factor insulin-like growth factor-I. Finally, the involvement of this hormone in M. leprae-induced SC survival was confirmed in experiments with neutralizing antibodies. Taken together, the results of this study delineate an important strategy for the successful colonization of M. leprae in the nerve based on the survival maintenance of the host cell through induction of IGF-I production.

Mycobacterium leprae infection of human Schwann cells depends on selective host kinases and pathogen-modulated endocytic pathways.

Mycobacterium leprae, an obligate intracellular pathogen, shows a unique tropism for Schwann cells (SC). This leads to the peripheral neuropathy disorder observed in leprosy. In this study, we investigated signal transduction events and the intracellular fate of M. leprae during the interaction of the microorganism with SC. First, we demonstrated that the human schwannoma cell line ST88-14 readily phagocytized the bacteria as observed by time-lapse microscopy, actin staining and electron microscopy. The effect of specific kinase inhibitors on M. leprae internalization was then investigated showing that functional protein tyrosine kinase, calcium-dependent protein kinase and phosphatidylinositol 3-kinase, but not cAMP-dependent protein kinase are essential for phagocytosis of the bacteria. Similar results were obtained when irradiated and live bacteria were compared and when M. leprae was pre-coated with recombinant histone-like-protein/laminin binding protein, a bacterial adhesin. In addition, experiments were performed to analyze the bacterial trafficking within the endosomal network by labeling the acidified intracellular compartments of M. leprae-infected SC with the Lysotracker acidotrophic probe. Acidification of vesicles containing live M. leprae was minimal in both RAW murine macrophages and SC, although phagosomes containing heat-killed bacteria seem to follow normal endocytic maturation. These data indicate that the invading bacteria interfere with normal endocytic pathway maturation of bacteria-containing phagosomes within SC.