Faculty Directory

Education

Degree	Institution	Major
M.D.	University of California San Francisco	Medicine
B.S.	Yale University	Biology

Post-Graduate Training

Training	Institution	Specialty
Residency	UCLA	Internal Medicine
Fellowship	UCLA	Infectious Diseases
Fellowship	UCLA	Postdoctoral Research Fellow

Awards

Name of Award/Honor	Awarding Organization
Merit Award	NIH/NIAID
Established Investigatorship Award, 1992-97	American Heart Association
Scholar, 1989-92	American Foundation for AIDS Research
Pfizer Scholars Award for New Faculty 1986-88	Pfizer
Young Investigator Award	American Society for Microbiology
Pfizer Medical Research Merit Award	PFIZER CORPORATION
Postdoctoral Research Fellowship 1984-86	American Social Health Association
National Merit Scholar

Lyme Disease/Borrelia burgdorferi
The Lyme disease spirochete B. urgdorferi is maintained in nature via an enzootic cycle in which it is transmitted by the nymphal stage of its vector, the deer tick Ixodes scapularis, to a mammalian host (typically the white-footed mouse Peromyscus leucopus) and then is acquired when a naïve larval tick feeds on an infected mouse. Infection of humans with B. burgdorferi is accidental and is not required for persistence of the spirochete in nature. In order to transit between its arthropod and mammalian hosts, spirochetes must decipher complex environmental cues delivered at the feeding site and, in response, undergo dramatic changes in their transcriptomes and proteomes. The principal objective of Lyme disease research conducted in the Radolf Laboratory is to understand these processes. The alternative sigma factor RpoS is a unifying genetic feature of this project. Signals delivered by the blood meal induce the expression of RpoS which, as the promoter-reading subunit of RNA polymerase, induces far-reaching changes in the bacterium’s transcriptome: (1) upregulation of approximately 100 B. burgdorferi genes that we believe are required for transmission of spirochetes from tick to mouse and/or the establishment of infection once within the mouse and (2) downregulation of approximately 30 tick-phase genes that spirochetes no longer need once they are inoculated into mice.

Critical to this work has been our development of green fluorescent protein (GFP) reporters that enable us to track live spirochetes in ticks and mice. Our live-imaging studies have fundamentally changed our understanding of the transmission process. In order to reach the mouse, spirochetes disseminate through the midgut into the salivary glands in order to access the salivary stream which they “ride” into the vertebrate host. We have found that dissemination of spirochetes in ticks is actually biphasic. In the first phase, which we have termed “adherence-mediated migration, spirochetes replicate in close association with differentiating midgut epithelial cells, “working” their way as aggregates or networks to the base of the epithelium. In the second phase, they transition into typically motile spirochetes, complete the penetration through the midgut, and then move on to the salivary glands en route to the mouse. Most recently, we have found that spirochetes lacking RpoS are deficient in this process and we are developing various strategies to identify the RpoS-dependent genes involved.

Syphilis/Treponema pallidum
The syphilis spirochete T. pallidum harbors many resemblances to B. burgdorferi but actually employs a markedly different parasitic strategy. Whereas B. burgdorferi is an enzootic pathogen, T. pallidum is an obligate pathogen of humans which cannot be cultivated in artificial medium. The modes of transmission of the two bacteria differ markedly as well: T. pallidum is transmitted from person-to-person by sexual activity, whereas B. burgdorferi is transmitted by an arthropod vector. Once within the host, T. pallidum begins to replicate locally, eventually causing a genital ulcer, called a chancre, the clinical hallmark of the primary stage of the disease. As the chancre develops, treponemes begin to make their way towards draining lymph nodes and blood vessels in order to spread systemically. Once within the blood, T. pallidum is extremely adept at invading virtually every organ system in the body, including the central nervous system, and establishing persistent infection that can cause serious, even life threatening, complications months to years later. We have designated T. pallidum “the stealth pathogen” because of its remarkable ability to evade host immune defenses.

Efforts in the Radolf Laboratory to explain T. pallidum’s stealth pathogenicity have focused on the bacterium’s unusual molecular architecture. Over the years, we have generated abundant evidence that the T. pallidum outer membrane differs markedly in structure and composition from its gram-negative counterparts (e.g., Escherichia coi). Not only does it lack lipopolysaccharide, the highly inflammatory glycolipid in the outer membranes of gram negative bacteria, it also contains a much lower density of integral membrane proteins that present few surface antigenic targets to the host immune system. Situated below the outer bilayer, where they are inaccessible to antibodies in intact organisms, are the bacterium’s major immunogens, many of which are periplasmic proteins tethered by N-terminal lipids to the cytoplasmic membrane. This work ushered in what we have termed “the quest” for T. pallidum outer membrane proteins, a project that has been ongoing for more than 20 years. Why a quest? Because identifying rare outer membrane proteins is so difficult and requires extraordinary commitment. Fortunately, we now have much more powerful tools to fulfill the quest, among which is the complete genomic sequence of T. pallidum. Genome mining, however, isn’t as easy as it sounds because, with one exception, there are no proteins in the T. pallidum genome with sequence relatedness to well characterized outer membrane proteins of gram-negatives. This work is complicated further by the fragility of the treponeme’s outer membrane. Our genereal strategy is to use bioinformatics algorithms to identify outer membrane protein candidates that then must be cloned, expressed, purified, structurally characterized, and localized in live treponemes. Why is this quest important? Two reasons. First, outer membrane proteins provide channels through which bacteria obtain nutrients. Second, we believe that these surface-exposed proteins, few as they are, are likely vaccine candidates. Given the explosive increase in syphilis cases in the United States and the world during the past decade, a vaccine would be a major weapon in our battle against this centuries old affliction of humans.

In order to fulfill its genetic destiny as a stealth pathogen, T. pallidum must acquire nutrients in every milieu within its obligate human host in which it finds itself, while fending off the host’s attempts to undermine its homeostasis. Recognition of this metabolic war between pathogen and host led us to explore other facets of T. pallidum virulence. One has been transition metal acquisition. Transition metals, such as iron, manganese, and zinc, are essential for life but are present in mammalian body fluids at exceedingly low concentrations. Bacterial pathogens, T. pallidum being no exception, employ highly developed strategems to obtain these nutrients. Our work along these lines has centered about characterizing two ABC transporters within the cytoplasmic membrane (Tro and Znu) that work cooperatively to meet the bacterium’s metal requirements. Lastly, our immune system uses toxic compounds called reactive oxygen species, to kill bacteria. T. pallidum has extremely robust enzymatic mechanisms for detoxifying reactive oxygen species. Understanding how these enzymes work and are regulated in response to host defenses is relevant to all bacterial diseases, not just syphilis.

Accepting students for Lab Rotations: Summer, '13, Fall '13, Spring '14

Lab Rotation Projects
Molecular Pathogenesis of Syphilis and Lyme Disease

1. Differential gene expression by Borrelia burgdorferi, the Lyme disease spirochete. B. burgdorferi undergoes dramatic changes in gene expression and protein composition as it cycles back and forth between its arthropod vector (deer ticks) and mammalian host (mice and other rodents). We have developed a variety of genetic techniques that, in conjunction with microarray analysis, are enabling us to decipher the patterns of borrelial gene expression at various points in the enzootic cycle, the mechanisms that regulate differential gene expression, and the relevant signal transduction mechanisms.

2. Outer membrane architecture of Treponema pallidum, the syphilis spirochete. We demonstrated a number of years ago that the T. pallidum outer membrane differs markedly in ultrastructure and composition from the “conventional” outer membranes of gram-negative bacteria, such as E. coli. We have identified a novel T. pallidum outer membrane protein that integrates into the outer membrane lipid bilayer via covalently bound lipids and amphipathic helices. This protein also appears to promote solute uptake by destabilizing the lipid bilayer, creating pores. Using model membrane systems, we would like to understand more about the structure-function relationships of this unusual molecule.

Journal Articles

Book Chapters

Conference Papers

Editorials

Letters

Notes

Reviews

Title or Abstract	Type	Sponsor/Event	Date/Year	Location
The going and coming of Lyme disease: differential gene expression, environmental sensing, and spirochete tracking	Talk	Department of Microbiology and Immunology	2011	University of Calgary, Calgary, CA.
The going and coming of Lyme disease: differential gene expression, environmental sensing, and spirochete tracking	Talk	Inter-city Infectious Diseases Conference	2011	University of Connecticut Health Center.
Tracking spirochetes and spirochete gene expression: illuminating the pathogenesis of Lyme disease	Talk	Department of Microbiology, LSU Veterinary School	2010	Baton Rouge, LA
Molecular architecture of Treponema pallidum: making a living as a stealth pathogen	Talk	Department of Pathology and Laboratory Medicine	2010	UT Houston Medical Center.
Tracking spirochetes and spirochete gene expression: illuminating the pathogenesis of Lyme disease	Talk	Department of Microbiology and Immunology	2009	University of Kentucky, Lexington, KY
Immune recognition of Borrelia burgdorferi, the Lyme disease spirochete by phagosomal signaling: signaling from the grave	Talk	Department of Microbiology and Immunology	2009	U. of MD School of Medicine, Baltimore, MD.
Tracking spirochetes and spirochete gene expression: illuminating the pathogenesis of Lyme disease	Talk	Department of Microbiology and Molecular Genetics	2009	Stony Brook University, Stony Brook, NY
Tracking spirochetes and spirochete gene expression: illuminating the pathogenesis of Lyme disease	Talk	Department of Oral Biology, School of Dental Medicine	2009	SUNY at Buffalo, Buffalo, NY
The Quest for Treponema pallidum outer membrane proteins: a reappraisal	Talk	Eighth Gordon Research Conference on the Biology of Spirochetes	2008	Ventura, CA.
Immune recognition of pathogenic spirochetes by phagosomal signaling	Talk	Department of Immunology	2008	UCHC, Farmington, CT.
Immune recognition of pathogenic spirochetes by phagosomal signaling	Talk	Forsyth Institute	2008	Harvard School of Dental Medicine, Boston, MA.
Summary/Highlights: Basic Science Track	Talk	17th meeting of the ISSTDR/10th IUSTI World Congress	2007	Seattle, WA
Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen	Talk	Department of Microbiology & Immunology Research Seminar	2007	Med. Coll. VA., Richmond, VA.
Treponema pallidum, the syphilis spirochete: making a living as a stealth pathogen	Talk	Department of Microbiology & Immunology Research Seminar	2007	Virginia Commonwealth University, Richmond, VA
Spirochetes and spirochetal diseases	Talk	Medical College of Virginia	2007	Virginia Commonwealth University, Richmond, VA.
Outer membrane proteins of Treponema pallidum, the syphilis spirochete	Talk	Hauptman-Woodward Institute	2007	Buffalo, NY
Recognition of pathogenic spirochetes by phagosomal signaling	Talk	Department of Veterinary and Animal Sciences	2007	University of Massachusetts, Amherst, MA.
Microbial Pathogenesis: a new frontier in translational research	Talk	Connecticut Children’s Medical Center	2007	Hartford, CT
Syphilis Pathogenesis: a post-genomics perspective	Talk	Infectious Diseases Grand Rounds	2007	New York Medical College, Valhalla, NY.
The Treponema pallidum outer membrane and what lies beneath	Talk	Symposium on Pathogenic Spirochetes	2006	UCLA Dept. Micro., Immunology, and Molecular Gen.
Immune recognition by pathogenic spirochetes: looking below the surface	Talk	Department of Medicine Research Seminar	2006	U. of Mass.Medical School, Worcester, MA.
Syphilis and Syphilis Research Sponsored by Drs. Socrates Herrara and Miriam Arevalo, Instituto de Inmunologia del Valle.	Talk	students and faculty at Universidad del Valle	2005	Cali Colombia
Innate and Adaptive Immunity: An Infectious Disease Doc’s Perspective Sponsored by Corporacion de Lucha Contra El SIDA, Cali Colombia.	Talk	X Curso Internacional de Enfermedades Infecciosas	2005	Cali Colombia
Innate and Adaptive Immunity in Syphilis and Lyme Disease (Dr. Carol Wu, organizer)	Talk	UCHC Faculty Research Seminar Series	2005	UCHC
Syphilis Research in the 21st Century: One Investigator’s Perspective	Talk		2005	Walter Reed Army Inst. for Res., Rockville, MD.
Syphilis Research in the 21st Century: One Investigator’s Perspective	Talk	CIDEIM	2005	Cali, Colombia.
Infectious Diseases in the Post-Genomics Era Sponsored by Corporacion de Lucha Contra El SIDA	Talk	XI Seminario Integral del Sida y	2005	Cali Colombia
Use of green fluorescent protein transcriptional reporters to study differential gene expression by Borrelia burgdorferi	Talk	NATO Advanced Research Workshop on the Molecular Biology of Spirochetes	2005	Prague, Czech Republic
The Innate-Adaptive Immune Interface in Syphilis and Lyme disease	Talk		2004	Albany Medical College, Albany, NY.
Innate and adaptive immunity: an introduction	Talk	CIDEIM	2004	Cali, Colombia
Syphilis-HIV Interactions: What we do and don’t know	Talk	IX Curso Internacional de Enfermedades Infecciosas	2004	X Seminario Integral del Sida y
Differential gene expression by Borrelia burgdorferi: new tools and new paradigms	Talk	Department of Microbiology and Molecular Genetics	2003	University of Dentistry and Medicine, New Jersey
20 years of syphilis research	Talk	Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDIEM),	2003	Cali, Colombia.
Chaired a session on host-pathogen interactions and presented an overview entitled “Lipoproteins, innate immunity, and the cutaneous immune response to Borrelia burgdorferi”	Talk	Fifth Gordon Research Conference on the Biology of Spirochetes	2002	Ventura, CA.
Differential expression by Borrelia burgdorferi and shuttle vector development: what goes around, comes around	Talk	Wadsworth Public Health Laboratories	2002	Albany, NY
Organized and convened a colloquium entitled Arthropod-vector interactions: the flip-side of human disease	Talk	102nd General Meeting of the American Society for Microbiology	2002	Salt Lake City, Utah.
Molecular pathogenesis of Lyme disease	Talk	Ninth International Conference on Lyme Borreliosis and other Tick-borne Diseases	2002	New York, NY.
The roll of toll-like receptors in innate inflammatory and immune responses to spirochetal infections	Talk	XXVIIth meeting of the Brazilian Society of Immunology	2002	Salvador, Brazil
Spirochetal lipoproteins as proinflammatory mediators in syphilis and Lyme disease	Talk	Dental Dean’s Seminar	2001	University of Connecticut Health Center.
TLR2 responses in vivo: bridging innate and adaptive immunity (Dr. D. Golenbock, organizer).	Talk	Toll-receptor club	2001	Boston University Medical Center
Spirochetal lipoproteins as proinflammatory agonists in syphilis and Lyme disease	Talk	Division of Rheumatology	2001	New England Medical Center, Boston, MA.
B. burgdorferi lipoproteins and innate immunity in Lyme disease	Talk	NIH-sponsored workshop on neuroborreliosis	2001	Airlie Center, Virginia
Development of a Borrelia burgdorferi shuttle vector: turning the tables	Talk	Department of Molecular and Cellular Biology	2001	University of Connecticut, Storrs
Spirochetal lipoproteins as proinflammatory agonists in syphilis and Lyme disease	Talk	Rheumatology Grand Rounds	2000	Yale University School of Medicine, New Haven, CT.
Structure-function relationships of Treponema pallidum membrane proteins	Talk	Fourth Gordon Research Conference on the Biology of Spirochetes	2000	Ventura, California
Treponema pallidum and Syphilis Research: lessons from the genome	Talk	UCHC GMB&B Faculty Research Seminar Series	2000
Treponema pallidum and syphilis research: Lessons from the genome	Talk	Department of Microbiology	2000	Indiana U. School of Medicine, Indianapolis, IN.
Spirochetal lipoproteins as proinflammatory agonists in syphilis and Lyme disease	Talk	Division of Infectious Diseases	2000	Indiana U. School of Medicine, Indianapolis, IN.
Molecular architecture of Treponema pallidum: implications for syphilis pathogenesis. Keynote address.	Talk	annual meeting of the Center for Excellence in Vaccine Research at UConn	2000	Storrs, CT
Molecular architecture of Treponema pallidum: implications for syphilis pathogenesis	Talk	Depts. of Biochemistry and Microbiology	1999	West Virginia U., Morgantown, W.Va.
Spirochetal lipoproteins as proinflammatory agonists in syphilis and Lyme disease	Talk	Infectious Diseases Division	1999	Boston University School of Medicine
Molecular architecture of Treponema pallidum: implications for syphilis pathogenesis	Talk	Oswaldo Cruz Foundation	1999	Salvador, Brazil.
Syphilis Pathogenesis and New Developments in Syphilis Diagnosis	Talk	Brazilian Congress of Microbiology	1999	Salvador, Brazil
Molecular architecture of Borrelia burgdorferi: implications for Lyme Disease pathogenesis	Talk	Dept. of Microbiology and Internal Medicine	1998	UCHC, Farmington, CT.
Molecular architecture of Borrelia burgdorferi: implications for Lyme Disease pathogenesis	Talk	Dept. of Biology and Dept. of Internal Medicine	1998	Brookhaven Nat. Lab. and SUNY at Stony Brook, NY.
Treponema pallidum biology: doing the best it can with what it’s got and Pathogenesis of syphilis (also served as co-organizer and co-Chair).	Talk	International Business Conference-sponsored symposium on Spirochete Diseases	1998
New model systems for studying mammalian host adaptation by Borrelia burgdorferi	Talk	seminar to the Depts. of Molecular Biology and Entomology	1998	Oklahoma State University, Stillwater, OK.
Identification of rare outer membrane proteins in isolated Treponema pallidum outer membranes - a reappraisal	Talk	Third Conference on the Biology of Spirochetes	1998	Ventura, CA
Syphilis Pathogenesis	Talk	graduate student course on bacterial pathogenesis	1998	NYU Skirball Institute
New model systems for studying differential gene expression by Borrelia burgdorferi	Talk		1998	Skirball Institute, NYU School of Medicine, NYC.
Treponema pallidum molecular architecture: implications for syphilis pathogenesis and A new model system for studying differential gene expression by Borrelia burgdorferi	Talk	Dept. of Microbiology and Immunology	1998	Medical College of Virginia.
Spirochetal Lipoproteins: Structure-function relationships and host responses Presented as part of a symposium on "Membrane-anchored Molecules"	Talk	Annual Meeting of the Society for General Microbiology	1997	Reading, UK.
Spirochetal lipoproteins as inflammatory mediators in syphilis and Lyme disease	Talk	Division of Infectious Diseases/Dept. of Microbiology & Immunology seminar	1997	University of North Carolina, Chapel Hill
A new animal model for studying Borrelia burgdorferi in the mammalian host-adapted state	Talk	Department of Biochemistry & Molecular Biology	1997	New York Medical College, Valhalla, NY.
A vaccine for syphilis: the never ending story Presented as part of a symposium entitled "Vaccines for Sexually Transmitted Diseases"	Talk	37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC),	1997	Toronto, CA
Spirochetal lipoproteins as inflammatory mediators in syphilis and Lyme disease	Talk	Division of Infectious Diseases/Department of Microbiology seminar	1997	LA State U. School of Medicine, New Orleans, LA.
Outer membrane ultrastructure as a virulence determinant of Treponema pallidum and Borrelia burgdorferi	Talk	Second Gordon Conference on the Biology of Spirochetes	1996	Ventura, CA
Lyme Disease 1996: the clouds are parting	Talk	McBee Lectureship	1996	Baylor Medical Center
Lyme Disease 1996	Talk	Dermatology Grand Rounds	1996	UT Southwestern and St. Paul's Medical Centers
Treponema pallidum molecular architecture: Implications for disease pathogenesis and vaccine development	Talk	Infectious Diseases Research Seminar Series	1996	Univ. of Cincinatti, Cincinatti, OH.
Syphilis and HIV: results of a prospective, multicenter, CDC sponsored study of syphilis and HIV infection Sponsored by the Division of Infectious Diseases, UT Southwestern Medical Center and the Dallas County Public Health Department.	Talk	Sexually Transmitted Diseases Seminar Series	1996	UT Southwestern Medical Center
Borrelia burgdorferi molecular Architecture and Lyme disease pathogenesis	Talk	Division of Infectious Diseases seminar	1995	SUNY at Downstate Medical Center
Syphilis and rare outer membrane proteins	Talk	Keystone Symposium entitled "Sexually Transmitted Diseases in the HIV Era"	1995	Keystone, Colorado
Treponema pallidum molecular architecture: Implications for syphilis pathogenesis	Talk		1995	SUNY at Stony Brook
The Molecular biology of Treponema pallidum: Where next?	Talk	International Society for STD Research	1995	New Orleans, LA
Outer membrane ultrastructure as a major virulence factor of Treponema pallidum	Talk	First Gordon Conference on the Biology of Spirochetes	1994	Ventura, CA.
Syphilis in the HIV Era	Talk	International Society for Infectious Diseases	1994	Prague, Czech Republic
Lyme Disease 1993: of mice and men. Presented at the annual meeting	Talk	Oklahoma Infectious Diseases Society	1993	Oklahoma
Surface components of Borrelia burgdorferi Sponsored by the Lyme Borreliosis Foundation and the Stamford, CT Dept. of Public Health.	Talk		1992	Stamford, CT
Treponema pallidum uItrastructure: Implications for syphilis pathogenesis.	Talk	annual meeting of the Texas chapter of the American Society of Microbiology	1992	San Antonio, TX
New Insights into the molecular architecture of Borrelia burgdorferi	Talk	symposium on the Immunobiology of Lyme Disease	1992	Cold Spring Harbor, NY.
Immunology and molecular biology of spirochetal lipoproteins	Talk	First Cold Spring Harbor Laboratory Symposium on the Immunobiology of Lyme Disease	1991	Cold Spring Harbor, N.Y.
Ultrastructure and molecular biology of Treponema pallidum: Implications for syphilis pathogenesis	Talk	Annual Meeting of the American for Microbiology	1991
Triton X-114 phase partitioning of spirochetal membrane proteins	Talk	7th International Conference on Partitioning in Aqueous Two-Phase Systems	1991	New Orleans, LA.
Participant and presented a synopsis of my research on T. pallidum molecular biology and ultrastructure.	Talk	NIH-sponsored symposium entitled "The Molecular Immunology of Sexually Transmitted Diseases"	1991	Rocky Mountain National Laboratories, Hamilton, MN
Molecular immunology of spirochetal lipoproteins	Talk	NIH-sponsored symposium on Lyme disease	1991	Rocky Mnt. National Lab., Hamilton, MT
Invited participant(unable to attend).	Talk	Molecular Biology of Spirochetes symposium	1991	Annecy, France
Spirochete ultrastructure and molecular biology: Implications for pathogenesis	Talk	Division of Infectious Diseases seminar	1991	Vanderbilt University, Nashville, TN.
Moderator Molecular biology of pathogens	Other	Annual Meeting of the American Society for Microbiology	1990	Anaheim, CA.
Syphilis and HIV Infection and Lyme disease 1990	Talk	Annual meeting of the Texas Infectious Diseases Society	1990	Bandera, TX.
Developing a molecular biology of syphilis	Talk	Infectious Diseases seminar	1990	Brown University, Providence, R.I.
Invited participant	Talk	NIH symposium on Lyme disease	1990	Bethesda, MD.
Spirochete lipoproteins: Molecular biology and Implications for disease pathogenesis	Talk	Department of Microbiology	1990	University of Alabama at Birmingham
Molecular and ultrastructural Analysis of the Treponema pallidum outer membrane presented at a World Health Organization-sponsored symposium	Talk	The Biology and the Pathogenicity of Treponemes	1989	University of Birmingham, Birmingham, UK.
Analysis of the Treponema pallidum outer membrane by freeze-fracture electron microscopy. Presented at a symposium entitled Special Topics in Modern Treponema Research	Talk	Annual Meeting of the American Society for Microbiology	1989	New Orleans, LA.
Towards a molecular biology of Treponema pallidum	Talk	Sexually Transmitted Diseases Seminar, Harborview Medical Center	1989	University of Washington, Seattle, WA.
Molecular biology of neurosyphilis	Talk	Medical Genetics Rounds	1989	UT Southwestern Medical Center
Participant, panel discussion on Syphilis and HIV Infection	Talk	Centers for Disease Control	1988	Atlanta, GA.
Syphilis 1987: Goodbye, Colombus.	Talk	Sexually Transmitted Diseases Seminar Series and Dallas County Public Health Department	1987	U.T. Southwestern Medical Center