Pamela Small Professor, Department of Microbiology The University of Tennessee PhD: Stanford University (1986) F323 Walters Life Sciences 1414 W. Cumberland Ave Knoxville, TN 37996 865-974-4042 psmall@utk.edu

Keywords:
Host-pathogen interactions, cellular microbiology, comparative microbial genomics, mycobacterial polyketides

Research Area:

Description of Research:
Among mycobacterial pathogens such as M. tuberculosis, M. leprae and M. ulcerans, it is becoming increasingly clear that lipids play a major role in virulence. In our laboratory we have identified a polyketide-derived macrolide, mycolactone, from M. ulcerans. Mycolactone causes cell death via apoptosis as well as immunosuppression. Information from the genome of M. tuberculosis suggests that similar molecules are also made by M. tuberculosis although the gene products have yet to be identified.

Research in our laboratory is focussed on the identification of polyketide virulence determinants in pathogenic mycobacteria and on understanding how these molecules contribute to the virulence. We are particularly interested in discovering the cellular mechanisms underlying mycolactone-mediated virulence. DNA microarrays of human genes are being used to identify the cellular pathways involved in mycolactone-mediated immunosuppression. Bacterial proteomics is also being investigated as a tool for studying the expression of mycolactone genes in M. ulcerans.

Evidence from the M. tuberculosis genome suggests that in M. tuberculosis polyketide synthase genes are highly mutable. We are interested in the underlying molecular epidemiology of polyketide genes in M. tuberculosis and other pathogenic mycobacteria particularly with respect to the role these molecules may play in virulence.

Selected Publications:

• George, K.M., D. Welty L. Pascopella, and P.L.C. Small. The Mycobacterium ulcerans mycolactone causes apoptosis in tissue culture cells and in guinea pig ulcers. Infect. Immun. 68: 877-883. 2000.


• Benowitz, A.B., S. Fidanze, Small, P.L.C., and Y. Kishi. Stereochemistry of the core structure of the mycolactones. J. Amer.Chem.Soc. 123:5128-5129. 2001.


• Dobos, K. M., P. L. Small, M. Deslauriers, F. D. Quinn, and C.H. Quinn. Mycobacterium ulcerans cytotoxicity in an adipose cell model. Infect. Immun. 69: 7182-7186. 2001.


• Fidanze, S., F. Song, M. Szlosek-Penaud, P.L.C. Small, and Y. Kishi. Complete structure of the mycolactones. J. Amer. Chem. Soc. 10117-10118. 2001.


• Snyder, D. Scott and P.L.C. Small. Staining of fibroblast mitochondria with LDS- 751. J. Immunol. Methods. 257:35-40. 2001


• Cadapan, L.D., R.L. Arslanian, J. R. Carney, S.M. Zavala, P.L. Small and P. Licari. Suspension cultivation of Mycobacterium ulcerans for the production of mycolactones. FEMS Micro Lett. 10246: 1-5. 2001.


• Fidanze, S., F. Song, M. Szlosek-Penaud, P.L.C. Small, and Y. Kishi. Complete structure of the mycolactones. J. Amer. Chem. Soc. 10117-10118. 2001.


• Cadapan, L.D., R.L. Arslanian, J. R. Carney, S.M. Zavala, P.L. Small and P. Licari. Suspension cultivation of Mycobacterium ulcerans for the production of mycolactones. FEMS Micro Lett. 10246: 1-5. 2001.


• Snyder, D. Scott and P.L.C. Small. Uptake and cellular actions of mycolactone on L929 fibroblasts. Microbial Pathogenesis.34:91-101, 2002.


• Cope, R.B., W. M. Haschek, and P.L.C. Small. Ultraviolet-B radiation enhances both the nodular and ulcerative forms of Mycobacterium ulcerans infection in a CrI:IAF (HA)-hrBR hairless guinea pig model of Buruli ulcer disease. Photodermatology, Photoimmunology and Photomedicine. 18:271-279. 2002.


• Mve-Obiang, A., R.L. Lee, F. Portaels, and P.L.C. Small. Heterogeneity of mycolactone toxins produced by Mycobacterium ulcerans: Implications for virulence. Infection and Immunity. 71: 774-783; 2003.