| Notes: | Advisor: Juliane Bubeck Wardenburg.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences, and The Pritzker School of Medicine, Department of Microbiology, 2015.
Dissertation Abstracts International, Volume: 76-08(E), Section: B.
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| Summary: | Staphylococcus aureus is a significant cause of bacteremia and sepsis leading to significant morbidity and mortality. Bloodstream infection is accompanied by multiple-organ dysfunction, characterized by endothelial injury, altered platelet function, and aberrant host inflammatory responses culminating in decreased tissue oxygenation and organ failure. The success of S. aureus as a bloodstream pathogen stems from the array of multifaceted virulence determinants possessed by the organism, however, the molecular mechanisms by which intravascular infection facilitates diverse cellular dysfunction and multiple organ injury remains unknown.
S. aureus [alpha]-hemolysin ([alpha]-toxin) is a highly conserved pore-forming toxin that utilizes ADAM10 as its cellular receptor. The toxin plays prominent roles in the progression of multiple invasive disease processes through its ability to pleiotropically target a broad range of host cells. Hla targets epithelial and endothelial cells, platelets and immune cells, leading to diverse alterations of cellular function dependent on the nature of the host cell that is intoxicated. While decades of research has uncovered multiple roles for [alpha]-toxin in cellular injury and dysfunction, the contribution of the toxin to the pathogenesis of staphylococcal sepsis has yet to be uncovered.
We show herein that staphylococcal [alpha]-toxin is required for full virulence in a mouse model of sepsis. Toxin binding to its receptor ADAM10 upregulates the receptor's metalloprotease activity on endothelial cells, resulting in VE-cadherin cleavage and concomitant loss of endothelial barrier function. Endothelial injury by [alpha]-toxin is accompanied by induction of pathologic platelet activation and neutrophil inflammatory signaling governed by the interaction of the toxin with its cellular receptor ADAM10 on these cell populations. Platelet intoxication prevents physiologic repair of damaged endothelium, and facilitates the formation of platelet-neutrophil aggregates that augment neutrophil IL-1[beta] production. These host cellular responses contribute to sepsis-associated acute lung and liver injury, which are mitigated by deletion of ADAM10 on platelets and myeloid lineage cells. While platelet or myeloid-specific ADAM10 knockout does not alter sepsis mortality, double knockout animals are highly protected. These observations highlight the unique ability of a single toxin to target multiple host cells in the vascular microenvironment through a common receptor, coordinating sepsis-associated multi-organ dysfunction and culminating in sepsis mortality.
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