The inflammasome in the host response against intracellular pathogens and the microbial mechanisms for its evasion

Abstract

Coxiella burnetii, Legionella pneumophila and Leishmania are intracellular pathogenic microbes that are etiological agents of important infections in humans. These microbes survive and replicate in macrophages and monocytes, within modified vacuoles showing lysosomal characteristics. Therefore, these pathogens are highly adapted to subvert host cell functions to facilitate intracellular replication. The mechanisms underlying microbial detection by the innate immune system and subversion are still largely unknown. We have previously found that the inflammasome is activated in response to Leishmania spp and L. pneumophila, but is not activated in the C. burnetii-infected macrophages in a process actively modulated by the bacteria (unpublished data). We have also generated preliminary data indicating that inhibition of the inflammasome activation is mediated by a C. burnetii effector protein that we named IcaA (Inhibition of Caspase Activation). In the current research proposal, we aim to investigate, characterize and determine the molecular mechanisms by which the inflammasome is activated in response to these pathogens as well as the mechanisms by which IcaA inhibits the inflammasome activation. Finally, we aim to develop and optimize an experimental model of C. burnetii infection in primary mouse alveolar macrophages to evaluate the importance of innate immune components (including those dependent on inflammasomes) in the restriction of microbial replication of in macrophages. The results generated may significantly contribute to our understanding of the biology and host response against these pathogenic microbes. Moreover, the identification of novel biological molecules that target the inflammasome may generate important information for a putative therapy for inflammasome-driven diseases such as Gout, type 2 diabetes and Alzheimer's. (AU)