Borrelia burgdorferi induces secretion of pro-urokinase-type plasminogen activator by human monocytes

Abstract

Borrelia burgdorferi is transmitted by infected ticks and causes Lyme disease. To infect distant organ sites, B. burgdorferi spirochetes must disseminate from the site of the tick bite. During dissemination from the dermal tissue, they breach tissue barriers, probably by proteolysis. The previous findings that spirochetes bind serum-derived plasminogen and that plasmin favors spirochetal invasiveness and infectivity suggested a role for plasmin in the pathogenicity of B. burgdorferi. Binding of plasminogen to spirochetes and activation into plasmin is favored in a microenvironment that is rich in plasminogen and plasminogen activators. Plasminogen is abundant in plasma and interstitial fluids, and it is increased in inflammatory exudates. Since B. burgdorferi does not express endogenous plasminogen activators, the conversion of spirochete-bound plasminogen depends on host-derived plasminogen activators. In this report, we show that both intact B. burgdorferi organisms and its recombinant outer surface lipoprotein A induce human monocytes to express and secrete urokinase-type plasminogen activator in its zymogen form (pro-uPA). Moreover, we demonstrate that the presence of B. burgdorferi accelerates the interaction between (pro-)uPA and plasmin(ogen), leading to spirochete-bound plasmin. In a pro-uPA-serum mixture, spirochete-bound plasmin activity is generated. Taken together, the data suggest that B. burgdorferi may induce pro-uPA in a monocyte-containing inflammatory site and that the spirochetal surface provides an appropriate milieu for subsequent interactions between (pro-)uPA and plasmin(ogen), which result in spirochete-bound plasmin even in the presence of inhibitors for plasminogen activators and plasmin.

Borrelia burgdorferi migrates into joint capsules and causes an up-regulation of interleukin-8 in synovial membranes of dogs experimentally infected with ticks

“…This implies that centrifugal spread of the migrating spirochete leads to colonization of the tissues. This is also supported by results of Klempner et al, who showed that B. burgdorferi possesses the ability to bind the host's plasminogen on its outer surface (17,25), which is enzymatically processed to surface-bound plasmin (13). Plasmin can degrade high-molecular-weight glycoproteins, which could improve the dissemination of B. burgdorferi in connective tissue.…”

Reciprocal upregulation of urokinase plasminogen activator and its inhibitor, PAI-2, by Borrelia burgdorferi affects bacterial penetration and host-inflammatory response

“…Using quantitative RT-PCR, we show that Borreliainduced transcription of uPA in monocytic cells terminates after 4 h of co-culturing with B. burgdorferi. This time frame of uPA transcriptional induction observed may require viable spirochetes as previous findings using lipidated OspA showed a delayed transcription of uPA that peaked at 4 h of stimulation (Fuchs et al, 1996). The degree of induction of levels and activity of uPA by B. burgdorferi appears to be in the same order as in clinical situations where different concentrations can be associated with progression of disease and as indicator of prognosis (Miyake et al, 1999).…”

Insights from a novel three-dimensional in vitro model of Lyme arthritis: Standardized analysis of cellular and molecular interactions betweenBorrelia burgdorferi and synovial explants and fibroblasts

“…However, these experimental approaches are limited by ethical considerations as well as the fact that not all data can be applied to the situation in humans. Most in vitro studies are based on findings in monolayer cell cultures(14–19). The major shortcoming of these experimental settings is the loss of the physiologic 3‐D arrangement of the cells, which leads to changes in morphology and function.…”