Intestinal epithelial cells must detect and respond to microbial pathogens that cause foodborne and waterborne diseases, yet also discriminate them from the trillions of other microbes in the intestine that are innocuous or even beneficial. The mechanisms by which host cells make this distinction are poorly understood. Our long-term goal is to better understand how pathogens are discriminated from other microbes by intestinal cells, as well as by other cell types. Closing this gap in our understanding may allow for improved treatment of infectious diseases, as well as better control of inflammatory disorders. Our central hypothesis is that a major strategy for discriminating pathogens from other microbes is through sensing perturbations of core host processes that are commonly targeted by pathogen-derived toxins. The objective here is to identify the mechanism by which the nematode C. elegans detects such pathogen-induced perturbations. C. elegans provides an excellent system to address this question because it relies on epithelial defense and is extremely tractable. We will also extend our findings to mammals, to investigate a similar protective host response. Our recent findings have shown that perturbation of core processes like mRNA translation triggers activation of the C. elegans bZIP transcription factor ZIP-2 to provide host defense (Dunbar et al, 2012). ZIP-2 upregulates a suite of genes involved in intracellular defense, and promotes resistance to infection (Estes et al, 2010). Our unpublished results suggest that ZIP-2 works together with CEBP-2, which is the C. elegans ortholog of mammalian C/EBP-?, a transcription factor that mediates acute response to infection in mammals. We hypothesize that 1) ZIP-2 and CEBP-2 form a heterodimeric transcription factor that promotes host defense, 2) ZIP-2 translation is upregulated upon infection by an upstream open reading frame (uORF) that acts as a sensor for translational attenuation, and 3) mammals deploy a similar host defense system. We will test our first hypothesis in Specific Aim 1, where we will examine CEBP-2 and ZIP-2 phenotypes, expression and interaction. We will test our second hypothesis in Specific Aim 2, where we investigate the underlying mechanisms of the surprising result that translational attenuation increases ZIP-2 protein levels. We will analyze the zip-2 uORF (Dunbar et al, 2012), and characterize hits from a genetic screen for regulators of ZIP- 2.
In Aim 3, we will build off our preliminary findings into mammals, testing a role for C/EBP-? in the protective response to toxins, and investigating the functional significance of this response in vivo. This approach is innovative, because it analyzes how cells detect perturbations in core processes targeted by pathogens, which is a newly appreciated mode of animal host defense. It also investigates the role and function of uORFs, which are found in 30-50% of all mouse and human genes, but poorly understood. The proposed research is significant because it will provide insight into how cells respond specifically to pathogenic attack, and may lead to new treatments for infections in the intestine as well as other tissues, to better combat infectious disease.

Public Health Relevance

Infectious diseases are responsible for over 25% of deaths worldwide. Such diseases are caused by pathogens that attack and disable core processes in host cells, which must detect these changes and respond appropriately to upregulate immunity and host defense. By identifying evolutionarily conserved mechanisms of pathogen detection, we will uncover fundamental principles of host defense, and identify new therapeutic avenues to combat infectious disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM114139-04
Application #
9532880
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Somers, Scott D
Project Start
2015-08-01
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Troemel, Emily (2018) Host-parasite interactions: an interview with Emily Troemel. BMC Biol 16:133
Kuo, Cheng-Ju; Hansen, Malene; Troemel, Emily (2018) Autophagy and innate immunity: Insights from invertebrate model organisms. Autophagy 14:233-242
Reddy, Kirthi C; Dror, Tal; Sowa, Jessica N et al. (2017) An Intracellular Pathogen Response Pathway Promotes Proteostasis in C. elegans. Curr Biol 27:3544-3553.e5
Reinke, Aaron W; Mak, Raymond; Troemel, Emily R et al. (2017) In vivo mapping of tissue- and subcellular-specific proteomes in Caenorhabditis elegans. Sci Adv 3:e1602426
Reinke, Aaron W; Balla, Keir M; Bennett, Eric J et al. (2017) Identification of microsporidia host-exposed proteins reveals a repertoire of rapidly evolving proteins. Nat Commun 8:14023
Balla, Keir M; Luallen, Robert J; Bakowski, Malina A et al. (2016) Cell-to-cell spread of microsporidia causes Caenorhabditis elegans organs to form syncytia. Nat Microbiol 1:16144
Botts, Michael R; Cohen, Lianne B; Probert, Christopher S et al. (2016) Microsporidia Intracellular Development Relies on Myc Interaction Network Transcription Factors in the Host. G3 (Bethesda) 6:2707-16
Reddy, Kirthi C; Dunbar, Tiffany L; Nargund, Amrita M et al. (2016) The C. elegans CCAAT-Enhancer-Binding Protein Gamma Is Required for Surveillance Immunity. Cell Rep 14:1581-1589
Stentiford, G D; Becnel, -J J; Weiss, L M et al. (2016) Microsporidia - Emergent Pathogens in the Global Food Chain. Trends Parasitol 32:336-348
Zhang, Gaotian; Sachse, Martin; Prevost, Marie-Christine et al. (2016) A Large Collection of Novel Nematode-Infecting Microsporidia and Their Diverse Interactions with Caenorhabditis elegans and Other Related Nematodes. PLoS Pathog 12:e1006093

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