Targeting M. Leprae survival strategies in the PNS

点击翻译按钮获取中文摘要

EXCEED THE SPACE PROVIDED. Leprosy remains an important global health problem, and represents a classical example of infectious neuro- degenerative diseases of the peripheral nervous syetm (PNS). Mycobacterium leprae infection of Schwann cell, the glial cell of the PNS, is the primary cause for the nerve damage in leprosy. We have recently shown that the non-myelinating Schwann cell, but not the myelinated Schwann cell, preferentially harbors M. leprae, and thus serves as the intracellular niche for persistent infection. Because M. leprae is an obligate intra- cellular pathogen with the longest doubling time and limited number of genes in its genome, the establishment of productive infection within non-myelinated Schwann cells is the key for bacterial survival. However, the mechanisms of M. leprae survival within Schwann cells are unknown. Targeting of M. leprae survival strategies will provide the rational to develop new therapeutics to combat the neurological injury and disease progression. To study these aspects, we used primary human Schwann cells (isolated and purified from human peripheral nerves) as a model, since they phenotypically resemble non-myelinated Schwann cells in vivo. Intracellular M. leprae in vitro maintain viability for several weeks without causing any apoptosis or cytopathic effect to Schwann cells. Microarray analysis using Affimatrix human GeneChips with cRNA prepared from primary human Schwann cells infected with viable M. leprae for 30 days, we showed that the majority of differentially expressed Schwann cells genes are (i) enzymes that regulate metabolic and respiratory functions, (ii) cell cycle regulators/inhibitors, (iii) growth/neurotropic factors, (iv) growth factor receptors and (v) associated transcriptional and signaling molecules. Therefore, we propose that once infected, M. leprae effectively use Schwann cell machinery in one hand to maintain the bacterial viability and the other hand to secure the intracellular niche for long-term bacterial survival by regulating Schwann cell growth. To study these, we will study the following: (1) M. leprae regulation of Schwann cell metabolic/ catabolic functions, (2) Regulation of human Schwann cell cycle by M. leprae, and (3) M. leprae-induced growth/neurotropic factors and their effects on Schwann cell signaling, growth and functions. These studies should provide novel insight into the persistent M. leprae infection in the PNS, nerve damage in leprosy patients, and the basic biology of glial cells. city, state) PERFORMANCE SITE ========================================Section End===========================================