The Activation of the Inflammasome during Rickettsial Infection

Rickettsiae are Gram-negative, obligately intracellular bacteria that infect endothelial cells and macrophages. The molecular mechanisms involved in interaction of rickettsiae with macrophages, however, remain poorly understood. In this dissertation, I have investigated the canonical and non-canonical inflammasome activation by rickettsiae in mouse macrophages. The central hypothesis is that activation and priming by lipopolysaccharide (LPS) of caspase-11 and ASC-dependent inflammasomes in macrophages is essential for host clearance of rickettsia through mediating the secretion of IL-1β, IL-18, and induction of pyroptosis. Specific Aim 1 focuses on the role of caspase-11-dependent inflammasome activation in host response against rickettsial infection and the activation mechanisms involved. The hypothesis of this aim is that caspase-11 is likely not protective in a mouse model of rickettsial infection. In vitro, inflammasome activation in mouse BMM is ASC dependent and partially caspase-11 dependent. Specific Aim 2 has more clearly demonstrated the role of rickettsial lipopolysaccharide in priming and activating the inflammasome in mouse macrophages. Rickettsial LPS can act as the inflammasome priming signal 1 component through TLR4, although other priming mechanisms do exist for inflammasome activation in macrophages during rickettsial infection. Additionally, rickettsial LPS transfected to the cytosol of macrophages indicates that rickettsial LPS can be sensed intracellularly by caspase-11, though the availability and structure of this ligand may contribute to low levels of activation through the caspase-11-dependent inflammasome activation pathway during infection. Taken together, our data, for the first time, illustrate the activation of inflammasome by rickettsiae in macrophages and the mechanisms involved.

Name thesis:degree_name

Experimental Pathology (Doctoral)

Level thesis:degree_level

Doctoral

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Smalley, Claire

• Rickettsia, Inflammasome

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/11179

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/11179