Mechanisms of increased microvascular permeability during acute Rickettsiosis

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Mechanisms of increased microvascular permeability during acute Rickettsiosis

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Title: Mechanisms of increased microvascular permeability during acute Rickettsiosis
Author: Michael Edward Woods
Abstract: Rickettsial diseases represent some of the most severe bacterial infections in man including Rocky Mountain spotted fever and epidemic typhus. Rickettsiae primarily target the microvascular endothelium leading to increased microvascular permeability, the mechanisms of which are completely unknown. We sought to determine the impact of host responses to infection on increasing microvascular permeability both in vitro and in vivo. Our work has revealed a role for TNF-á, IL-1â, and IFN-ã as mediators of anti-rickettsial immunity that contribute to increased microvascular permeability in a dose-dependent manner by modulating the function of interendothelial adherens junctions. The permeability-inducing effects of these cytokines appear to occur independently of nitric oxide production since inhibition of iNOS does not prevent cytokine-mediated increases in permeability. Additionally we have shown that iNOS expression in vivo is associated with sites of rickettsial invasion, which also correlates with the leakage of endogenous serum protein. The lack of significantly higher levels of serum cytokines suggests this is primarily a localized response confined to areas of leukocyte infiltration. Likewise we have demonstrated a role for innate endothelial cell responses in modulating adherens junctions following rickettsial invasion. Human endothelial cells infected with rickettsiae produced significantly higher levels of VEGF and IL-6, two cytokines which can have a profound impact on adherens junction stability. This was associated with increased kinase activity in the form of protein kinase C, Src, and focal adhesion kinase. Inhibition of Src during R. rickettsii infection led to a decreased rate of endothelial permeability however this did not prevent rickettsiae-mediated cell death. Finally, we have identified several novel pathways modulated after rickettsial infection that were not previously thought to be important to rickettsial pathogenesis. Future work will be aimed at determining the relative contribution of these pathways to the endothelial dysfunction accrued during rickettsial infection. The work generated here provides a solid foundation for future endeavors aimed at alleviating the vascular dysfunction experienced during severe rickettsial infection.
URI: http://hdl.handle.net/2152.3/270
Date: 2007-11-02

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