The Early Dissemination Defect Attributed to Disruption of Decorin-Binding Proteins Is Abolished in Chronic Murine Lyme Borreliosis

Abstract

The laboratory mouse model of Lyme disease has revealed that Borrelia burgdorferi differentially expresses numerous outer surface proteins that influence different stages of infection (tick-borne transmission, tissue colonization, dissemination, persistence, and tick acquisition). Deletion of two such outer surface proteins, decorin-binding proteins A and B (DbpA/B), has been documented to decrease infectivity, impede early dissemination, and, possibly, prevent persistence. In this study, DbpA/B-deficient spirochetes were confirmed to exhibit an early dissemination defect in immunocompetent, but not immunodeficient, mice, and the defect was found to resolve with chronicity. Development of disease (arthritis and carditis) was attenuated only in the early stage of infection with DbpA/B-deficient spirochetes in both types of mice. Persistence of the DbpA/B-deficient spirochetes occurred in both immunocompetent and immunodeficient mice in a manner indistinguishable from that of wild-type spirochetes. Dissemination through the lymphatic system was evaluated as an underlying mechanism for the early dissemination defect. At 12 h, 3 days, 7 days, and 14 days postinoculation, DbpA/B-deficient spirochetes were significantly less prevalent and in lower numbers in lymph nodes than wild-type spirochetes. However, in immunodeficient mice, deficiency of DbpA/B did not significantly decrease the prevalence or spirochete numbers in lymph nodes. Complementation of DbpA/B restored a wild-type phenotype. Thus, the results indicated that deficiency of DbpA/B allows the acquired immune response to restrict early dissemination of spirochetes, which appears to be at least partially mediated through the lymphatic system.

Borrelia burgdorferi RevA Significantly Affects Pathogenicity and Host Response in the Mouse Model of Lyme Disease

“…Here again, immune evasion could be key; the revA-deficient mutant may be inducing a more pronounced, but tissue-specific, inflammatory response that causes damage to the host while failing to clear the bacteria. Studies of the establishment and early dissemination of bacteria deficient in other adhesins, such as DbpA and BBK32, have hinted at roles in avoiding immune clearance (24,68). Further research employing bioluminescent whole-body imaging, combined with comprehensive examination of tissuespecific pathology and immune responses, could provide insights into the role of RevA in both dissemination and colonization in the early stages of infection.…”

BB0744 Affects Tissue Tropism and Spatial Distribution of Borrelia burgdorferi

“…Tissues contain diversity within their ECM, with various subunits and ratios of collagens, fibronectin, integrins, fibrinogen, and laminin (65). ECM-binding adhesins have been characterized in many pathogens, and some have been discovered in B. burgdorferi, including DbpA, BBK32, P66, Bgp, BBB07, and BBA33 (21)(22)(23)(24)(25)(26)(27)54). B. burgdorferi has an outer surface rich in lipoproteins, many of which are hypothesized to interact with host structures and provide for optimal adhesion and/or immune evasion.…”

“…B. burgdorferi may travel through the lymphatic system not only for dissemination but also to interfere with the im-mune response and gain a survival advantage for spirochetes infecting all tissues (39). Recent studies have also found that, in contrast to BBK32, DbpA is involved in transmission via the lymphatic system, indicating that distinct modalities may be operative in borrelial dissemination (23,32,33,36). It is probable that B. burgdorferi has adapted to multiple routes of dissemination, as quick systemic infection is an important function for a pathogen that travels from host to host by tick bite at random locations.…”

“…BBK32 has been implicated as one of the proteins involved in blood vessel dissemination, and spirochetes have been visualized adhering to and transmigrating across blood vessel epithelial cell layers during infection (36). However, there is increasing evidence that B. burgdorferi may also migrate through the lymphatic system (16,23,37).…”

“…The ability of B. burgdorferi to evade the immune response and colonize tissues lies within the numerous lipoproteins that adorn its outer surface (20). Many of these lipoproteins have been characterized as ECM (extracellular matrix) adhesins, including those that bind to decorin (DbpA), fibronectin (BBK32), glycosaminoglycans (Bgp; BBK32; DbpA), and integrins (BBB07, P66), as well as many others with unknown host ligands (21)(22)(23)(24)(25)(26)(27). B. burgdorferi also expresses on its surface a variable surface antigen, VlsE, and five different factor H binding proteins designated complement regulator-acquiring surface proteins, which are involved in the evasion of complement-dependent killing (28,29).…”