Identifier

etd-1109101-145509

Degree

Doctor of Philosophy (PhD)

Department

Biological Sciences

Document Type

Dissertation

Abstract

Globally, millions of leprosy patients suffer irreversible peripheral nerve damage resulting in blindness or other disabilities as a consequence of Mycobacterium leprae infection. Schwann cells, the neural target of M. leprae, have a central role in leprosy histopathology including axonotrophy, altered myelin architecture and demyelination. The mechanisms of nerve damage have not been fully elucidated but appear to be the direct result of M. leprae within Schwann cells or a combined effect with an aggressive immune response to M. leprae within the nerves. There is no standardized in vitro model for the study of M. leprae interactions with the Schwann cell that preserves the viability of M. leprae. Recent studies have determined that 33° C is permissive for maintenance of short-term M. leprae viability in axenic medium. Using this information, we developed a Schwann cell infection model that preserves the metabolic activity of M. leprae for up to 3 weeks in cultures, maintains functional abilities of Schwann cells to interact with neurons in culture and mimics cooler temperature areas where infection is observed in patients. When this model was used to study the impact of M. leprae infection on Schwann cells, Schwann cells had altered interactions with other Schwann cells and altered gene expression encoding several important adhesion molecules such as neural cell adhesion molecule (NCAM), neural-cadherin (N-cadherin) and glial fibrillary acidic protein (GFAP). However, M. leprae-infected Schwann cells were able to align and associate with neurons in culture, proliferate along these neurons and subsequently produce myelin in a manner comparable to control cultures. Established myelinated Schwann cell/neuron co-cultures, maintained at 33° C, did not demonstrate any apparent alterations in Schwann cell/neuron interactions nor myelin architecture due to M. leprae infection. These results indicate that M. leprae infection at the multiplicity of infection used for these studies does not appear to have detrimental effects on Schwann cell functional capabilities in the peripheral nerve. Therefore, the neuropathy observed in leprosy is most likely due to an aggressive immune response to infection within the nerve and not direct effects of M. leprae upon the Schwann cell.

Date

2001

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Diana L. Williams

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