The overall goal of this project is to understand molecular mechanisms of how the innate immune system senses and responds to bacterial pathogens and the evasion strategies utilized by bacterial pathogens to avoid immune detection. In particular we use Yersinia pseudotuberculosis, which expresses many of the same virulence factors as its close relative and plague pathogen Yersinia pestis, as a model to understand the host- pathogen interface and discover shared features of host innate immune responses to Gram-negative bacterial pathogens. The rapid expansion of multi-drug resistance among Gram-negative bacteria has increased the importance of developing new approaches to antimicrobial therapeutics, and understanding how the innate immune system initially detects bacterial pathogens and the corresponding pathogen evasion strategies holds promise for identifying novel antimicrobials. The Type III secretion system (T3SS) is a broadly conserved virulence determinant that is essential for virulence of many Gram-negative bacterial pathogens from E. coli to Y. pestis, and injects virulence factors into host cells that disrupt cellular signling pathways. However, T3SS activities can also be sensed by cytosolic pattern recognition receptors of the Nod-like receptor (NLR) family and induce host immune responses. Previous studies demonstrated that the Y. pseudotuberculosis and Y. pestis T3SS induces activation of an NLRP3-dependent inflammasome, resulting in cell death and caspase-1 dependent cytokine secretion. Furthermore, studies demonstrated that the essential Yersinia virulence factor YopK, which modulates the pore-forming activity of the T3SS and limits translocation of other Yop effector proteins, prevents inflammasome activation. Inflammasome activation plays an important role in host defense against Yersinia, as the virulence defect of YopK-deficient bacteria is restored in mice that lack inflammasome components. However, the molecular basis for how cells sense the activity of Yersinia's T3SS and how YopK prevents this sensing is not known. We propose three Specific Aims to address this important gap in our knowledge. First we will test the hypothesis that delivery of translocon components into the host cell cytosol activates the NLRP3 inflammasome through disruption of intracellular compartments. Second we will test the hypothesis that YopK prevents NLRP3 inflammasome activation by binding to the translocon and limiting injection of translocon components into the cell. Third, we will test te hypothesis that inflammasome activation in vivo controls Yersinia infection via production of caspase-1 dependent cytokines that induce activation of specific immune cell subsets that promote bacterial clearance.
Many Gram-negative bacterial infections that affect public health are caused by pathogens that utilize the type III secretion systems as a key virulence determinant. Defining how Yersinia YopK interferes with inflammasome sensing of type III secretion will provide a foundation for rational antimicrobial drug design that could target a conserved virulence activity of many bacterial pathogens that impact public health.
|Han, Seong-Ji; Glatman Zaretsky, Arielle; Andrade-Oliveira, Vinicius et al. (2017) White Adipose Tissue Is a Reservoir for Memory T Cells and Promotes Protective Memory Responses to Infection. Immunity 47:1154-1168.e6|
|Mowel, Walter K; McCright, Sam J; Kotzin, Jonathan J et al. (2017) Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA. Immunity 47:435-449.e8|
|Feeley, Eric M; Pilla-Moffett, Danielle M; Zwack, Erin E et al. (2017) Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems. Proc Natl Acad Sci U S A 114:E1698-E1706|
|Zwack, Erin E; Feeley, Eric M; Burton, Amanda R et al. (2017) Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components. Infect Immun 85:|
|Peterson, Lance W; Philip, Naomi H; DeLaney, Alexandra et al. (2017) RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense. J Exp Med 214:3171-3182|
|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|
|Philip, Naomi H; DeLaney, Alexandra; Peterson, Lance W et al. (2016) Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death. PLoS Pathog 12:e1005910|
|Peterson, Lance W; Philip, Naomi H; Dillon, Christopher P et al. (2016) Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis. J Immunol 197:4110-4117|
|Zwack, Erin E; Snyder, Annelise G; Wynosky-Dolfi, Meghan A et al. (2015) Inflammasome activation in response to the Yersinia type III secretion system requires hyperinjection of translocon proteins YopB and YopD. MBio 6:e02095-14|
|Rosadini, Charles V; Zanoni, Ivan; Odendall, Charlotte et al. (2015) A Single Bacterial Immune Evasion Strategy Dismantles Both MyD88 and TRIF Signaling Pathways Downstream of TLR4. Cell Host Microbe 18:682-93|
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