Chaconas, GeorgeTan, Xi2021-08-262021-08-262021-08-19Tan, X. (2021). Studies on Hematogenous Dissemination of Lyme Disease Spirochetes (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.http://hdl.handle.net/1880/113769Lyme disease (LD), caused by various members of the genus Borrelia, is the most prevalent tick-transmitted illness in North America and Europe (Groshong & Blevins, 2014, Stanek et al., 2011). There is an increasing risk of LD in Canada. In 2014, the Government of Canada launched a national communication campaign to raise social awareness and promote individual preventive behaviors toward LD. Hematogenous dissemination is important for infection by Borrelia burgdorferi (B. burgdorferi). B. burgdorferi can attach to the vascular endothelium and disseminate into a variety of tissue types. B. burgdorferi hematogenous dissemination is a multistep process and consists of several successive stages: transient (tethering plus dragging) interactions, followed by stationary adhesion and/or extravasation (Norman et al., 2008, Coburn et al., 2013). However, the mechanism of borrelial vascular adhesion and extravasation remained unclear. We are using intravital microscopy (IVM) (Kumar et al., 2015, Secklehner et al., 2017, Stolp & Melican, 2016) to identify and characterize B. burgdorferi adhesins, which are believed to be involved in vascular adhesion, transmigration as well as tissue tropism (Coburn et al., 2013, Caine & Coburn, 2016). From the B. burgdorferi side, we have shown that OspC is a dermatan sulfate- (DS-) and fibronectin- (FN-) binding adhesin that is required for vascular transmigration and joint colonization in mice (Lin et al., 2020). We also identified that VlsE, a well-known antigenically variable outer surface lipoprotein, is a DS-binding adhesin that efficiently promotes transient adhesion to the microvasculature via its DS binding activity in vivo. Moreover, on the host side, we have shown that instead of phagocytizing B. burgdorferi, host neutrophils are involved in producing specific cytokines (TNF-α, MCP-1, IL-10) that activate the endothelium and potentiate B. burgdorferi escape into the surrounding tissue. Spirochete escape is not induced by paracellular permeability and appears to occur via a transcellular pathway. Neutrophil repurposing to promote bacterial extravasation represents a new and innovative pathogenic strategy (Tan et al., 2021). Our findings provide insight into the mechanism of Borrelia hematogenous dissemination and how LD spirochetes employ host immune cells for vascular extravasation.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.Lyme DiseaseIntravital imagingin vivo studyMicrobiologydoctoral thesis10.11575/PRISM/39123