Michael V. Norgard, Ph.D.
Professor and Chair of Microbiology

Office:  214-648-5900
Fax:  214-648-5905
Email: michael.norgard@utsouthwestern.edu

Syphilis and Lyme disease are chronic, complex infections caused by the spirochetal bacteria Treponema pallidum and Borrelia burgdorferi, respectively.  While syphilis and Lyme disease are transmitted differently (i.e., sexually or through the bite of a tick), they share many common features.  These include penetration of the organism through skin, dissemination via the bloodstream, and immune evasion leading to chronic infection.  Acute and chronic inflammatory responses are associated with both diseases.

Little is known about the virulence factors or immune responses operative in the immunopathogenesis of syphilis and Lyme disease.  The paucity of information about syphilis stems primarily from the inability to cultivate T. pallidum in vitro.  Although B. burgdorferi can be cultivated in vitro, its complex life cycle (i.e., in ticks and in mammals) has hampered understanding its virulence traits.  Also, identification of the proinflammatory molecules of both organisms may hold the keys to clarifying virulence factors, to understanding the invasive and chronic natures of T. pallidum and B. burgdorferi, to explaining spirochetal immunopathogenesis, and to understanding potential spirochetal control through vaccine development.

A major goal of our laboratory program is to identify, characterize, and isolate spirochetal membrane proteins of biological significance to the immunopathogenesis processes of syphilis and Lyme disease and the virulence traits of the causative agents.  In this regard, we discovered that the major integral membrane proteins of both T. pallidum and B. burgdorferi are lipoproteins (proteolipids).  Bacterial lipoproteins are known to exhibit potent biological activities, such as the ability to activate B cells, macrophages, and other immune effector cells.  In syphilis, this has important implications not only to immunopathogenesis, but also for cellular events that likely contribute to HIV transmission (syphilis is an important cofactor for HIV transmission).  In the case of B. burgdorferi, certain lipoproteins are upregulated when the spirochete resides in ticks, whereas others are upregulated as the organism prepares itself to invade mammalian tissues.  Pertinent to this reciprocal regulation, we recently discovered an alternative sigma factor (RpoN-RpoS) regulatory pathway that controls the expression of key lipoprotein virulence factors in B. burgdoreri.  The complex gene regulation systems governing such differential antigen expression are critical for sustaining B. burgdorferi in its very different niches of ticks and mammals.  The elucidation of such systems will reveal much about the parasitic strategies of this important human pathogen.

Contemporary approaches in molecular biology, structural biology, immunology, and cell biology are being used for the identification, isolation, and characterization of membrane proteins and lipoproteins of T. pallidum and B. burgdorferi of potential relevance to virulence expression, immunopathogenesis, and vaccine development.  Structural and functional studies of selected integral membrane proteins are underway to understand how the peculiar membrane biology of T. pallidum and B. burgdorferi contributes to the host-parasite relationship, tissue dissemination, and immune evasion.  Given that both T. pallidum and B. burgdorferi have dual membrane systems that differ markedly from those of Gram-negative bacteria, research emphasis also is being placed on discerning the membrane topologies of key integral membrane proteins/lipoproteins.  Lastly, various molecular methodologies are being applied to improve the diagnosis of syphilis, congenital syphilis, and Lyme disease.

Finally, our lab recently is engaged in the national biodefense initiative.  Francisella tularensis is a Category A select agent of potential bioterrorism application.  It is easily weaponized and was previously the focus of biowarfare research in the former Soviet Union.  Infection with F. tularensis, also known as rabbit fever, is a zoonosis of small wild animals, but causes a serious, life-threatening infection when humans are inadvertently exposed.  Our program involves the elucidation of outer membrane proteins of F. tularensis that contribute to virulence of the organism and/or that may serve as new acellular vaccine formulations for tularemia.  This work is being conducted under strict biological safety level-3 containment.

News Publications:

UT Southwestern researchers receive $15.1 million in federal grants to study biothreats 

UT Southwestern researchers uncover key to survival ability of bacterium that causes Lyme disease

Scientists identify potential key to Lyme disease

Selected Publications:

Hübner, A., X. Yang, D.M. Nolen, T.G. Popova, F.C. Cabello, and M.V. Norgard. 2001. Expression of Borrelia burgdorferi OspC and DbpA is controlled by a RpoN-RpoS regulatory pathway.  Proc.Natl.Acad.Sci.U.S.A. 98:12724-12729.

Revel, A.T., A.M. Talaat, and M.V. Norgard. 2002. DNA microarray analysis of differential gene expression in Borrelia burgdorferi, the Lyme disease spirochete.  Proc.Natl.Acad.Sci.U.S.A. 99:1562-1567.

Yang, X.F., S.M. Alani, and M.V. Norgard.  2003.  The response regulator Rrp2 is essential for the expression of major membrane lipoproteins in Borrelia burgdorferi. 
Proc.Natl.Acad.Sci.U.S.A. 100:11001-11006.

Yang, X.F., U. Pal, S.M. Alani, E. Fikrig, and M.V. Norgard.  2004.  Essential Role for OspA/B in the Life Cycle of the Lyme Disease Spirochete.  Journal of Experimental Medicine 119:641-648.

Revel, A.T., J.S. Blevins, C. Almazan, L. Neil, K.M. Kocan, J. de la Fuente, K.E. Hagman, and M.V. Norgard.  2005.  BptA (bbe16) is essential for the persistence of the Lyme disease spirochete, Borrelia burgdorferi, in its natural tick vector.  Proc.Natl.Acad.Sci.U.S.A. 102:6972-6977.

Deka,R.K., C.A. Brautigam, X.F. Yang, J.S. Blevins, M. Machius, D.R. Tomchick, and M.V. Norgard. 2006. The PnrA (Tp0319; TmpC) lipoprotein represents a new family of bacterial purine nucleoside receptor encoded within an ATP-binding cassette (ABC)-like operon in Treponema pallidum.  J. Biol. Chem. 281:8072-8081.

Huntley, J.F., P.G. Conley, K.E. Hagman, and M.V. Norgard. 2007. Characterization of Francisella tularensis outer membrane proteins.  J. Bacteriol. 189:561-574.

Machius, M., C.A. Brautigam, D.R. Tomchick, P. Ward, Z. Otwinowski, J.S. Blevins, R.K. Deka, and M.V. Norgard. 2007. Structural and biochemical basis for polyamine binding to the Tp0655 lipoprotein of Treponema pallidum: putative role for Tp0655 (TpPotD) as a polyamine receptor.  J. Mol. Biol. 373:681-694.

Huntley, J.F., P.G. Conley, D.A. Rasko, K.E. Hagman, M.A. Apicella, and M.V. Norgard. 2008. Native outer membrane proteins protect mice against pulmonary challenge with virulent Type A Francisella tularensis.  Infection and Immunity 76:3664-3671.

Ouyang, Z., M. He, T. Oman, X.F. Yang, and M.V. Norgard. 2009.  A manganese transporter, BB0219 (BmtA), is required for virulence by the Lyme disease spirochete, Borrelia burgdorferi.  Proc.Natl.Acad.Sci.U.S.A. (In Press)