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.
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