Lyme disease is the most common vector-borne disease in the U.S. and and an important public health problem whose incidence continues to increase. In our preliminary work, we have shown that Borrelia burgdorferi, the causative agent of Lyme disease, induces host proteases from a family of enzymes called matrix metalloproteinases and that these enzymes, which are activated as part of the host immune response, are responsible for much of the cartilage degradation and arthritis caused by the organism. We have identified signaling pathways and receptors involved in the recognition of B. burgdorferi and activation of the host immune response. Interestingly, the most widely studied receptor for borrelial products, toll-like receptor 2 (TLR2) is not strictly required for the development of arthritis and release of cytokines and chemokines. We identified a previously unrecognized receptor of B. burgdorferi products, integrin a3b1, and showed that it plays a major role in induction of inflammatory mediators. In this proposal, we examine these two innate immune signaling pathways, integrin a3b1 and TLRs, and determine their contributions to the development of Lyme arthritis and control of infection. Animal studies in other organisms have suggested that integrin signaling may play a major role in inflammation with only a minor impact on control of infection whereas TLR signaling is the opposite, with a major role in control of infection and a lesser role in inflammation. In the first specific aim, we will test the role of a putative integrin a3b1 binding ligand of B. burgdorferi that we have identified. We will construct deletion mutants of the identified binding protein and test the ability of the mutant and a complemented mutant to infect, disseminate and cause arthritis in a mouse model. In the second aim, we will systematically examine signaling pathways activated by recognition of B. burgdorferi through integrin a3b1 and TLRs. Recent studies suggest that the innate immune response is shaped by """"""""cross-talk"""""""" between different families of receptors. Our preliminary data suggests that there is an interaction between signaling from integrin a3b1 and TLRs. Using information garnered from examining the intersections in the pathways that are activated by each receptor and the timing of activation, we will test specific hypotheses as to how these two pathways may intersect. Because pathology in Lyme arthritis (and many other forms of arthritis) is predominantly due to activation of the host immune system, by better understanding the pathways that direct inflammation and that control infection, we hope to identify areas of divergence that will be targets for future development of therapies that can reduce the pathogenesis of disease without delaying recovery from infection.
Recent evidence has shown that for inflammation, once thought to be critical for the control of bacterial infections, more is not necessarily better and that high degrees of inflammation do not necessarily confer better protection against infection, but may, in fact, worsen symptoms. We will study two signaling pathways, integrin a3b1 and TLRs, that are important in recognizing Borrelia burgdorferi, the causative agent of Lyme disease, and determine their contributions to inflammation and control of infection. These studies may identify potential targets for reducing inflammation without hindering clearance of infection of bacterial septic arthritis.
