A Systems Biology Approach to Infectious Diseases Research
EMSL Project ID
42294
Abstract
We describe an integrated program for coupling advanced capabilities in high-throughput transcriptomics, proteomics, and metabolomics with a comprehensive informatics infrastructure and a sophisticated approach to computational reconstruction and modeling of metabolic and gene regulatory networks. These powerful tools will be directed at delineating the mechanisms by which two related pathogens, Salmonella and Yersinia, adapt to the intracellular environment upon infecting macrophages and then manipulate that environment to facilitate their own survival and replication. The insights derived from modeling these behaviors may lead to the identification of novel therapeutic targets. The overall objectives are to: 1) Develop genome-scale metabolic and regulatory network reconstructions for Salmonella and Yersinia to provide the computational foundation for our systems biology approach; 2) Develop and disseminate 'sample matched' global datasets for Salmonella and Yersinia using transcriptomics, proteomics, and metabolomics technologies to provide the experimental foundation for our systems biology approach; 3) Produce and characterize knock-out mutations in regulatory genes predicted to be essential for systemic infection in mouse models for Salmonella enterica and Yersinia pestis; and 4) Use the network reconstructions, omics results, and phenotype changes in knock-out mutants to refine computational models of pathogenesis for Salmonella and Yersinia. EMSL world class capabilities in proteomics, NMR for structure and metabolomics, and advanced computation are well recognized. While all of these areas are included in the proposal the real benefit of using EMSL's capabilities is the team oriented nature of the operations; the project described above requires multiple-disciplines and multiple-strategies. These capabilities with the high quality team are why we request to perform this research in collaboration with EMSL.
Project Details
Project type
Exploratory Research
Start Date
2010-12-16
End Date
2011-12-18
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Adkins JN, H Mottaz, TO Metz, CK Ansong, NP Manes, RD Smith, and F Heffron. 2010. "Performing Comparative Peptidomics Analyses of Salmonella from Different Growth Conditions." Chapter 2 in Peptidomics: Methods and Protocols, Methods in Molecular Biology, vol. 615, ed. Mikhail Soloviev, pp. 13-27. Humana Press, Inc., New York, NY.
Ansong C, AC Rutledge, HD Mitchell, S Chauhan, MB Jones, YM Kim, K Mcateer, BL Deatherage, JL DuBois, HM Brewer, BC Frank, JE McDermott, TO Metz, SN Peterson, RD Smith, VL Motin, and JN Adkins. 2013. "A multi-omic systems approach to elucidating Yersinia virulence mechanisms." Molecular Biosystems 9(1):44-54. doi:10.1039/C2MB25287B
Ansong C, N Tolic, SO Purvine, S Porwollik, MB Jones, H Yoon, SH Payne, JL Martin, MC Burnet, ME Monroe, P Venepally, RD Smith, S Peterson, F Heffron, M Mcclelland, and JN Adkins. 2011. "Experimental annotation of post-translational features and translated coding regions in the pathogen Salmonella Typhimurium." BMC Genomics 12:Art. No. 433. doi:10.1186/1471-2164-12-433
Ansong C, S Wu, D Meng, X Liu, HM Brewer, BLD Kaiser, ES Nakayasu, JR Cort, PA Pevzner, RD Smith, F Heffron, JN Adkins, and L Pasa-Tolic. 2013. "Top-down proteomics reveals a unique protein S-thiolation switch in Salmonella Typimurium in response to infection-like conditions." Proceedings of the National Academy of Sciences of the United States of America 110(25):10153-10158. doi:10.1073/pnas.1221210110
Bordbar A, ML Mo, ES Nakayasu, AC Rutledge, YM Kim, TO Metz, MB Jones, BC Frank, RD Smith, SN Peterson, DR Hyduke, JN Adkins, and BO Palsson. 2012. "Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation." Molecular Systems Biology 8(558):, doi:10.1038/msb.2012.21
Brown RN, JA Sanford, JH Park, BL Deatherage, BL Champion, RD Smith, F Heffron, and JN Adkins. 2012. "A Comprehensive Subcellular Proteomic Survey of Salmonella Grown under Phagosome-Mimicking versus Standard Laboratory Conditions." International Journal of Proteomics 2012:Article ID 123076. doi:10.1155/2012/123076
Buchko GW, G Niemann, ES Baker, ME Belov, RD Smith, F Heffron, JN Adkins, and JE McDermott. 2010. "A multi-pronged search for a common structural motif in the secretion signal of Salmonella enterica serovar Typhimurium type III effector proteins." Molecular Biosystems 6(12):2448-2458. doi:10.1039/c0mb00097c
Charusanti P, S Chauhan, K Mcateer, JA Lerman, DR Hyduke, VL Motin, C Ansong, JN Adkins, and BO Palsson. 2011. "An Experimentally-Supported Genome-Scale Metabolic Network Reconstruction for Yersinia pestis CO92." BMC Systems Biology 5:Article No. 163. doi:10.1186/1752-0509-5-163
Kidwai AS, IT Mushamiri, G Niemann, RN Brown, JN Adkins, and F Heffron. 2013. "Diverse Secreted Effectors Are Required for Salmonella Persistence in a Mouse Infection Model." PLoS One 8(8):e70753. doi:10.1371/journal.pone.0070753
Kim YM, TO Metz, Z Hu, SD Wiedner, JS Kim, RD Smith, WF Morgan, and Q Zhang. 2011. "Formation of dehydroalanine from mimosine and cysteine: artifacts in gas chromatography/mass spectrometry based metabolomics ." Rapid Communications in Mass Spectrometry 25:2561-2564. doi:10.1002/rcm.5134
Latif H, JA Lerman, VA Portnoy, Y Tarasova, H Nagarajan, AC Rutledge, RD Smith, JN Adkins, DH Lee, Y Qiu, BO Palsson, and K Zengler. 2013. "The genome organization of Thermotoga maritima reflects its lifestyle." PLoS Genetics 9(4):e1003485. doi:10.1371/journal.pgen.1003485; Epub 2013 April 25.
Li J, ES Nakayasu, CC Overall, R Johnson, AS Kidwai, JE McDermott, C Ansong, F Heffron, E Cambronne, and JN Adkins. 2015. "Global analysis of Salmonella alternative sigma factor E on protein translation." Journal of Proteome Research 14(4):1716-1726. doi:10.1021/pr5010423
Michalska K, RN Brown, H Li, R Jedrzejczak, G Niemann, F Heffron, JR Cort, JN Adkins, G Babnigg, and A Joachimiak. 2013. "New sub-family of lysozyme-like proteins shows no lytic activity – crystallographic and biochemical study of STM3605 protein from Salmonella Typhimurium." Journal of Structural and Functional Genomics 14(1):1-10. doi:10.1007/s10969-013-9151-0. Epub 2013 April 10.
Nakayasu ES, C Ansong, JN Brown, F Yang, D Lopez-Ferrer, W Qian, RD Smith, and JN Adkins. 2013. "Evaluation of selected binding domains for the analysis of ubiquitinated proteomes." Journal of the American Society for Mass Spectrometry. doi:10.1007/s13361-013-0619-8. Epub ahead of print
Nakayasu ES, RN Brown, C Ansong, MA Sydor, S Imtiaz, C Mihai, RL Sontag, KK Hixson, ME Monroe, T Sobreira, G Orr, VA Petyuk, F Yang, RD Smith, and JN Adkins. 2013. "Multi-omic data integration links Deleted in Breast Cancer 1 (DBC1) Degradation to Chromatin Remodeling in Inflammatory Response." Molecular & Cellular Proteomics. MCP 12(8):2136-2147. doi:10.1074/mcp.M112.026138
Nakayasu ES, R Tempel, XA Cambronne, VA Petyuk, MB Jones, MA Gritsenko, ME Monroe, F Yang, RD Smith, JN Adkins, and F Heffron. 2013. "Comparative phosphoproteomics reveals components of host cell invasion and post-transcriptional regulation during Francisella infection." Molecular and Cellular Proteomics 12(11):3297-3309. doi:10.1074/mcp.M113.029850
Nakayasu ES, S Wu, MA Sydor, AK Shukla, KK Weitz, RJ Moore, KK Hixson, JS Kim, VA Petyuk, ME Monroe, L Pasa-Tolic, W Qian, RD Smith, JN Adkins, and C Ansong. 2014. "A Method to determine lysine acetylation stoichiometries." International Journal of Proteomics 2014(Article ID 730725):, doi:10.1155/2014/730725
Niemann G, RN Brown, IT Mushamiri, NT Nguyen, R Taiwo, A Stufkens, RD Smith, JN Adkins, JE McDermott, and F Heffron. 2013. "RNA Type III Secretion Signals that require Hfq." Journal of Bacteriology 195(10):2119-2125. doi:10.1128/JB.00024-13
Wu J., A. Sabag-Daigle, M. Borton, L. Kop, B.E. Szkoda, B. Kaiser, and S.R. Lindemann, et al. 2018. "Salmonella-mediated inflammation eliminates competitors for fructose-asparagine in the gut." Infection and Immunity 86, no. 7:e00945-17. PNNL-SA-129012. doi:10.1128/IAI.00945-17