Recognition of pathogens by host defenses and subsequent activation of caspase-1 is important to resolve bacterial infection. Despite this, pathogens have developed mechanisms to prevent activation of caspase-1 to ensure survival and replication. An example of such is the effector YopM, an important virulence determinant of pathogenic Yersinia. YopM inhibits activation of caspase-1, yet the molecular mechanisms underlying this process remain largely unknown. We recently identified the host scaffolding protein IQGAP1 as a novel binding partner of YopM and found IQGAP1 to be important for activation of caspase-1 in response to Yersinia infection. These findings suggest that YopM inhibits activation of caspase-1 through targeting of IQGAP1. Given the importance of caspase-1 activation for host protection, understanding how IQGAP1 regulates activation of caspase-1 along with how pathogens subvert this process could aid the development of therapeutic strategies to combat bacterial infections. To accomplish this goal, three aims have been developed.
Aim 1 seeks to identify the role of IQGAP1 for host protection against Yersinia.
Aim 2 will determine the molecular mechanism of how IQGAP1 regulates activation of caspase-1 and how YopM disrupts this process.
Aim 3 focuses on the importance of IQGAP1 for activation of caspase-1 in response to Salmonella, which also possess an effector that targets IQGAP1. Accomplishing these aims will provide mechanistic insight on how IQGAP1 regulates activation of caspase-1 and will contribute to development of novel therapeutic strategies against infectious disease.
Inhibition of caspase-1 activation by bacterial pathogens is an important virulence mechanism, yet it remains understudied. This proposal is designed to investigate the role of IQGAP1 on regulation of caspase-1 activation in response to bacterial infection and how pathogens inhibit this process through the action of virulence effectors. Understanding this process is a fundamental component of infectious disease research and can lead to the identification of novel therapeutic targets.
|Schoberle, Taylor J; Chung, Lawton K; McPhee, Joseph B et al. (2016) Uncovering an Important Role for YopJ in the Inhibition of Caspase-1 in Activated Macrophages and Promoting Yersinia pseudotuberculosis Virulence. Infect Immun 84:1062-1072|
|Chung, Lawton K; Park, Yong Hwan; Zheng, Yueting et al. (2016) The Yersinia Virulence Factor YopM Hijacks Host Kinases to Inhibit Type III Effector-Triggered Activation of the Pyrin Inflammasome. Cell Host Microbe 20:296-306|
|Chung, Lawton K; Bliska, James B (2016) Yersinia versus host immunity: how a pathogen evades or triggers a protective response. Curr Opin Microbiol 29:56-62|