Pathogenic Shigellae and Yersiniae are one ofthe leading causes of foodborne diseases. While these diseases can be theoretically treated with antibiotics, the high incidence of the multidrug-resistant strains means that development of new antimicrobial treatments is critical. Bacteria corrupt numerous biochemical pathways of the host and understanding of these mechanisms directly contributes to the novel target drug discovery as well as it facilitates research on the established drug targets. However, many important aspects ofthe bacteria-host protein interactions remain unknown. Deubiquitinating enzymes (DUBs) regulate ubiquitination, a reversible modification that controls protein function, stability and localization. Our long-term goal is to understand the functions of DUBs in bacterial infection in order to facilitate discovery of novel therapies and diagnostics. The overall objective in this proposal is to determine the functions of DUBs in the foodborne diseases caused by Shigella and Yersinia by using an integrated proteomics approach and functional studies. Our central hypothesis is that human DUBs, such as 0TUB1, and their associated protein networks are central to virulence in shigellosis and yersiniosis, and that DUB activity is regulated by bacteria and host, consequently determining the disease outcome. Assessment of DUB-associated protein networks and their role in pathogenesis is novel and innovative. We will use two very different enteropathogens to unveil conserved as well as strain-specific biological functions of the DUBs. The rationale for the proposed research is that once we know functions and downstream pathways of DUBs affected by these infections, we can quantify the relevance of DUBs to these diseases and apply this information to a rational drug design.

Public Health Relevance

This comprehensive study of deubiquitinating enzymes involved in infections with Shigella and Yersinia will provide characterization of novel host responses to enterobacterial infections and insights into the hostpathogen interplay. It signifies an importance for translational medicine due to its contribution to finding protein targets for new chemotherapeutics, clearly required for an effective treatment of these infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103646-02
Application #
8743218
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mississippi State University
Department
Type
DUNS #
City
Mississippi State
State
MS
Country
United States
Zip Code
Bryant, Joseph C; Dabbs, Ridge C; Oswalt, Katie L et al. (2016) Pyruvate oxidase of Streptococcus pneumoniae contributes to pneumolysin release. BMC Microbiol 16:271
Wright, Morgan L; Pendarvis, Ken; Nanduri, Bindu et al. (2016) The Effect of Oxygen on Bile Resistance in Listeria monocytogenes. J Proteomics Bioinform 9:107-119
Seo, Keun Seok (2016) Monkey Feeding Assay for Testing Emetic Activity of Staphylococcal Enterotoxin. Methods Mol Biol 1396:125-31
Park, Joo Youn; Seo, Keun Seok (2016) Quantification of a Selective Expansion of T Cell Receptor Vβ by Superantigen Using Real-Time PCR. Methods Mol Biol 1396:167-80
Alugubelly, Navatha; Hercik, Kamil; Kibler, Peter et al. (2016) Analysis of differentially expressed proteins in Yersinia enterocolitica-infected HeLa cells. Biochim Biophys Acta 1864:562-9
Brown, Lindsey R; Gunnell, Steven M; Cassella, Adam N et al. (2016) AdcAII of Streptococcus pneumoniae Affects Pneumococcal Invasiveness. PLoS One 11:e0146785
Nanduri, Bindu; Shack, Leslie A; Rai, Aswathy N et al. (2016) Use of focused ultrasonication in activity-based profiling of deubiquitinating enzymes in tissue. Anal Biochem 515:9-13
Dhital, Saphala; Stokes, John V; Park, Nogi et al. (2016) Cannabidiol (CBD) induces functional Tregs in response to low-level T cell activation. Cell Immunol :
Moon, Bo Youn; Park, Joo Youn; Robinson, D Ashley et al. (2016) Mobilization of Genomic Islands of Staphylococcus aureus by Temperate Bacteriophage. PLoS One 11:e0151409
Ferguson, Lucas; Olivier, Alicia K; Genova, Suzanne et al. (2016) Pathogenesis of Influenza D Virus in Cattle. J Virol 90:5636-42

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