Bacterium-ECM interactions during infection by the Lyme disease spirochete

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Borrelia burgdorferi, the agent of Lyme disease, causes a chronic multisystemic illness, and its interaction with several components of extracellular matrix (ECM), such as fibronectin (Fn), the proteoglycan decorin, and glycosaminoglycans (GAGs), is thought to promote infection of diverse tissues. Several B. burgdorferi molecules that may promote this binding have been identified biochemically, including the GAG-binding protein Bgp, the decorin binding proteins DbpA and DbpB, and the fibronectin binding protein BBK32. We found that B. burgdorferi harboring an insertion in bgp remained infectious in mice, indicating that Bgp is not required for colonization. Consistent with this, B. burgdorferi binds more efficiently to GAGs upon adaptation to the host environment, but without demonstrable induction of bgp, suggesting that other adhesins may contribute to GAG binding. In fact, by expressing DbpA, DbpB or BBK32 on the surface of a high-passage, otherwise nonadherent B. burgdorferi strain, we demonstrated that in addition to their known ECM targets, all three are capable of promoting bacterial attachment to GAGs. The GAG-binding activity of DbpA is subject to allelic variation, and the GAG- and fibronectin-binding activities of BBK32 are apparently separable. We have recently generated targeted mutations of bgp, dbpA/dbpB and bbk32 in infectious B. burgdorferi strain backgrounds. To identify which components of ECM are physiologic receptors of B. burgdorferi adhesion, and whether their identity varies with different target tissues, we will generate derivatives of BBK32 that have lost Fn- and/or GAG-binding activity, and derivatives of DbpA and B that have lost decorin- and/or GAG- binding activity. Mice will be infected with B. burgdorferi bbk32 or dbpA/B mutants to assess the roles of these adhesins during infection. If bbk32, dbpA, /and/or dbpB are required for colonization of one or more tissues, variants of these genes that result in selective loss of GAG-, decorin- and/or Fn-binding activity will be tested for their ability to complement the colonization defect. By developing detailed knowledge of the interactions that are critical to colonization and disease of the Lyme disease spirochete, these studies may lead to novel therapeutic strategies aimed at preventing colonization by this important pathogen. Such studies may also shed light on general principles that govern tissue-specific infection by bacterial pathogens.