The Roles of Decorin and DbpA/B in Dissemination and Persistence of Borrelia burgdorferi

Borrelia burgdorferi, the etiologic agent of Lyme disease, is a tick-vectored, spirochetal pathogen that establishes chronic extracellular infection in a multitude of hosts. From the earliest disease descriptions, spirochetes were consistently identified within collagen-rich connective tissues, often aligned in parallel with collagen bundles. Localization of spirochetes within connective tissues is observed in multiple different stages of borreliosis, including initial infection, tissue colonization, dissemination and persistence. This recognized preference has lead many to postulate that the interaction between B. burgdorferi and the extracellular matrix (ECM) within connective tissues is integral to Lyme borreliosis. Attention has focused on evaluation of the interactions between borrelial adhesins and ECM ligands at the spirochete-tick interface and at the spirochete-host interface during initial infection. Far less is known about the role of borrelial adhesin and ECM ligand interactions in dissemination and persistence within the mammalian host. The following research was designed to evaluate the contribution of one adhesin – ligand pair, Decorin-binding protein A/B and decorin, to dissemination and persistence.;Decorin binding proteins A and B (DbpA/B) are well-characterized borrelial adhesins that were initially identified by their interaction with the proteoglycan decorin. A primary role for DbpA/B in dissemination has been indicated. In prior studies, spirochetes deficient in DbpA/B were unable to be recovered from tissues distant to the inoculation site in the early stages of borreliosis, representing an early dissemination defect. Within the scope of this research, the early dissemination defect of DbpA/B-deficient spirochetes was demonstrated to occur only in immunocompetent mice and not in immunodeficient mice. Attenuated disease associated with DbpA/B-deficient spirochetes was also documented in both immunocompetent and immunodeficient mice during early stages of infection. In both types of mice, the dissemination defect and disease attenuation were abolished with chronicity. Persistence of DbpA/B-deficient spirochetes was shown to occur in a manner equivalent to wild type. One proposed mechanism to account for the early dissemination defect was restricted migration through the lymphatic system. During early stages of infection, DbpA/B-deficient spirochetes were significantly less prevalent and in lower numbers in lymph nodes from immunocompetent mice. This pattern of reduced DbpA/B-deficient spirochete prevalence or numbers within lymph nodes was not observed in immunodeficient mice. The wild-type phenotype was restored by complementation of DbpA/B. Therefore, the early dissemination defect was attributed, at least in part, to restriction of spirochetal lymphatic migration by the acquired immune response. The data presented here indirectly suggests that DbpA/B facilitates survival of B. burgdorferi within the lymphatic route of dissemination.;The proteoglycan decorin is an ECM component that "decorates" collagen fibers. A direct association between the number of spirochetes and the expression level of decorin in chronically-infected laboratory mice has been documented previously, suggesting that decorin could be an essential component of protective microenvironments. Focusing on the cardiovascular system, this work demonstrated that B. burgdorferi persisted in a random distribution within connective tissue-rich microenvironments of the aortic tunica adventitia, epicardium, endocardium and myocardial interstitium, confirming connective-tissue tropism during chronic infection. In these microenvironments, spirochetes colocalized with decorin, not collagen I, providing additional evidence that decorin is a defining factor for protective niches. Localization within these decorin-rich microenvironments was induced by passive immunization of immunodeficient mice with B. burgdorferi-specific immune serum, indicating that localization in protective microenvironments is antibody-driven. Simultaneous antibody-mediated clearance of decorin-poor microenvironments was observed. With waning B. burgdorferi-specific antibody titers, the number of spirochetes in tissue was shown to rise and was accompanied by repopulation of the previously-cleared decorin-poor microenvironments. Thus, the connective tissue-tropism of B. burgdorferi during chronic infection is at least partially determined by decorin and is driven by theB. burgdorferi-specific antibody response. Fluctuation of spirochete populations and microenvironmental localization in response to the presence of B. burgdorferi-specific antibody represents the first experimentally-induced example of borrelial recrudescence.