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Justin D. Radolf
Professor of Medicine and Center for Microbial Pathogenesis
jradolf@up.uchc.edu

• M.D. University of California, San Francisco
• Immunology Graduate Program
• Skeletal, Craniofacial & Oral Biology Graduate Program
• Genetics and Developmental Biology Graduate Program
• Accepting Lab Rotation Students: Summer '08, Fall '08, Spring '09

Areas of Interest:
Lyme disease and venereal syphilis, illnesses caused by the spirochetal pathogens Borrelia burgdorferi and Treponema pallidum, respectively, are the principal foci of research in the Radolf laboratory. A major area of interest emanates from the recognition that clinical manifestations in Lyme disease and syphilis are mediated largely, if not exclusively, by the host's local and systemic inflammatory responses to the spirochete. A number of years ago we discovered that a large proportion of the membrane proteins in both spirochetes are lipid-modified and we subsequently demonstrated that lipoproteins are the major proinflammatory mediators in Lyme disease and syphilis. Subsequently, we identified the pattern recognition receptors (PRRs) and signaling pathways that enable these pathogen-associated molecular patterns (PAMPs) to active innate immune cells. These studies revealed the cellular activation by lipoproteins and synthetic lipoprotein analogs involves the GPI-linked protein CD14 acting in concert with Toll-like receptors 2 (TLRs) and 1. Ongoing studies are intended to identify the exact cellular compartments in which these signaling processes occur; quite surprisingly, these studies also have provided evidence for TLR-independent signaling pathways triggered only by live organisms. We are also developing innovative research strategies for assessing how spirochetes and spirochetal lipoproteins active immune cells within the skin, a major target organ of syphilis and Lyme disease. 

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.

3. The major objective of our immunology research is to understand the innate immune responses elicited by infection with Treponema pallidum and Borrelia burgdorferi, the causes of venereal syphilis and Lyme diseasse, respectively, and how these innate responses “instruct” the development of adaptive immunity. These proinflammatory processes are believed to be central to both disease pathogenesis (tissue destruction, symptom development) and disease resolution (clearance of spirochetes). Much of this work centers about our discoveries (i) that T. pallidum and B. burgdorferi express an abundance of lipid-modified proteins (lipoproteins) and (ii) that these lipoproteins or pathogen-associated molecular patterns (PAMPs) activate innate immune cells via the pattern recognitions receptors (PRRs) CD14 and Toll-like receptor 2 (TLR2). However, recent studies suggest that spirochetes also have the capacity to trigger innate immune processes via TLR-independent pathways. The interaction of TLR-dependent and –independent pathways appears to be critical for controlling the course of infection and determining the severity of clinical manifestations.

Publications

Selected References:

Rafii-El-Idrissi Benhnia, Wroblewski D, Akhtar MN, Patel RA, Lavezzi W, Gangloff SC, Goyert SM, Caimano MJ, Radolf JD and Sellati TJ. Signaling through CD14 attenuates the inflammatory response to Borrelia burgdorferi, the agent of Lyme disease. J Immunol 2005; 174:1539-1548.

Caimano MJ, Eggers CH, Hazlett KRO, and Radolf JD. RposBb is not central to the general stress response in Borrelia burgdorferi but does control expression of one or more virulence determinants. Infect Immun 2004; 72:6433-6445.

Grimm D, Eggers CH, Caimano MJ, Tilly K, Stewart PE, Elias AF, Radolf JD, and Rosa PA. Experimentally assessing the roles of linear plasmids lp25 and lp28-1 of Borrelia burgdorferi throughout the infectious cycle. Infect Immun 2004; 72:5938-5946.

Eggers CH, Caimano MJ, and Radolf JD. Analysis of promoter elements involved in the transcriptional initiation of RpoS-dependent Borrelia burgdorferi genes. J Bacteriol 2004; 186:7390-7402.

Salazar JC, Pope CD, Sellati TJ, Feder HM, Jr., Kiely TG, Dardick KR, Buckman RL, Moore MW, Caimano MJ, Pope JG, Krause PJ, Radolf JD and The Lyme Disease Network. Co-evolution of markers of innate and adaptive immunity in skin and peripheral blood of patients with erythema migrans. J Immunol 2003; 171: 2660-2670.

Narasimhan S, Caimano MJ, Liang FT, Santiago F, Laskowski M, Philipp MT,Pachner AR, Radolf JD, and Fikrig E. Borrelia burgdorferi transcriptome in the central nervous system of non-human primates. Proc Natl Acad Sci (USA) 2003:100:15953-15958.

Hazlett KRO, Rusnak F, Kehres DG, Bearden SW, La Vake CJ, La Vake ME, Maguire ME, Perry RD, and Radolf J D. The Treponema pallidum tro operon encodes a multiple metal transporter, a Zn-dependent transcriptional repressor, and a semi-autonomously expressed phosphoglycerate mutase. J Biol Chem 2003; 278:20687-20695.

Narasimhan S, Caimano MJ, Liang FT, Santiago F, Laskowski M, Philipp MT,Pachner AR, Radolf JD, and Fikrig E. Borrelia burgdorferi transcriptome in the central nervous system of non-human primates. Proc Natl Acad Sci (USA) 2003;100:15953-15958.