Lyme disease (LD), a tick-borne infection caused by the spirochetal bacterium Borrelia burgdorferi, is a multisystem chronic inflammatory disorder that affects the skin, joints, heart, and nervous system. Although many aspects of LD pathogenesis remain ill-defined, it is generally accepted that clinical manifestations result primarily from the host's local immune response to spirochetes in infected tissues. In vitro evidence suggests that the impetus for this local immune response is recognition of B. burgdorferi's major membrane immunogens (i.e., lipoproteins) by the pattern recognition receptor (PRR) CD14, a glycosylphosphatidyl inositol-anchored protein on the surface of monocytes/macrophages and neutrophils. Subsequent interaction between lipoprotein-CD14 complexes and the transmembrane transducing element Toll-like receptor 2 (TLR2) triggers a signaling cascade resulting in secretion of pro-inflammatory cytokines; these events likely contribute to the tissue and end-organ damage associated with LD. Despite the primacy and importance of lipoprotein binding to CD14 for immune cell activation in vitro, the consequences of this interaction during natural infection are entirely unknown. The overall objective of this proposal is to eliminate this gap in our knowledge through characterization of CD14's role in recognizing B. burgdorferi and initiating appropriate host defenses during borrelial infection. Toward achieving our objective, we have observed that CD14-deficient C3H/HeN (disease-susceptible) mice infected with B. burgdorferi via Ixodes scapularis ticks develop more severe and persistent disease compared with their wild type counterparts. Furthermore, peritoneal macrophages from CD14-deficient mice produced more proinflammatory TNF-alpha and less anti-inflammatory IL-10 than cells from wild type animals. Complementary studies using C57BL/6 (disease-resistant) mice are underway. These counterintuitive results suggest that CD14 is in fact dispensable for the initiation of disease and raise the intriguing possibility that signaling through this PRR may instead serve to down-modulate potentially damaging inflammatory cascades and protect the host from persistent infection. Based upon our findings, we hypothesize that engagement of the CD14-TLR2 signaling pathway provides negative feedback responsible for modulating the intensity and duration of inflammatory responses to B. burgdorferi. This hypothesis will be tested through pursuit of the following Specific Aims: 1) define the in vivo role of CD14 in modulating the clinical course and severity of Lyme disease, 2) characterize the ability of Borrelia burgdorferi-initiated CD14 signaling to modulate TLR2 expression and 3) identify components of the CD14 signaling cascade responsible for regulation of TLR2 and downstream inflammatory responses. It is our expectation that completion of these studies will identify the full complement of CD14 function as it relates to the development and resolution of disease triggered by borrelial infection and determine whether CD14-TLR2 signaling is requisite for establishment of disease susceptible/resistant phenotypes in mice. The rationale underlying this work is the belief that a better understanding of the immune processes that contribute to LD pathogenesis will serve as the basis for translational research that will yield improved control strategies and therapeutics to combat this chronic inflammatory disorder.
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NIH ExPorter