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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Alexander, William A
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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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