Head, Molecular Biol Reseach Section
The focus of research in my laboratory is the study of the molecular pathogenesis of Mycobacterium leprae. This research has led to the elucidation of molecular mechanisms of drug resistance of M. leprae and the development of molecular assays for rapid detection of M. leprae and its susceptibility to dapsone and rifampin directly from biological specimens. In addition, assays have been developed for detection of M. leprae viability. Several of these assays are utilized by the NHDP to provide information which can improve patient care.
Our research also involves the study of M. leprae genomics and transcriptomics utilizing bioinformatics and surrogate genetics to better understand M. leprae's preference for its primary host cells (peripheral macrophages and Schwann cells of the peripheral nervous system) and its ability to survive and grow within these host cells. These studies have identified a mechanism for the defective heat shock response in this pathogen which appears to contribute to its preference for peripheral sites of infection. These studies have also demonstrated that not only does M. leprae have the largest number of pseudogenes in any bacterial genome it also has the largest number of transcribed pseudogenes documented to date.
Recently we have determined the comprehensive transcriptome of M. leprae during exponential growth in the nude mouse footpad infection model as well as that of M. leprae that were held in mycobacterial medium using RNA-Seq technologies. It is anticipated that results from this area of research will expand our knowledge of the nutritional requirements for M. leprae growth, help identify nutritional deficiencies of axenic medium and thereby help to identify a defined medium for host-free culture of M. leprae. In addition, the transcriptome of M. leprae within the mouse foot pad will be potentially useful to identify novel therapeutic targets and for studying various aspects of M. leprae/host interactions and pathogenesis.
Williams DL, Pittman TL, Gillis TP, Matsuoka M, Kashiwabara Y. Simultaneous detection of Mycobacterium leprae and its susceptibility to dapsone using DNA heteroduplex analysis.
J Clin Microbiol. 2001 39(6):2083-8.
Williams DL, Pittman T, Deshotel M, Oby-Robinson S, Smith I, Husson R. Molecular basis of the defective heat stress response in Mycobacterium leprae. J. Bacti. 2007, 189:8818-27.
Martinez A, Lahiri R , Pittman T, Scollard D, Truman R, Moraes MO, Williams DL. Molecular Determination of Mycobacterium leprae Viability Using Real-Time PCR. J Clin Micro 2009. doi:10.1128/JCM.00512.
Williams DL, Slayden R. Amin A, Martinez A N, Pittman T, Mira A, Mitra A, Nagaraja V, Morrison N, Moraes M, Gillis TP. 2009. Implications of high level pseudogene transcription in Mycobacterium leprae. BMC Genomics 2009, 10:397.