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RNA Deep Sequencing and Metabolomic Profiling of Microgravity-Induced Regulation of the Host-Pathogen Interaction: An Integrated Systems Approach (NNX13AM01G)
Principal Investigator
Research Area:
Cell and molecular biology
Species Studied
Scientific Name: Salmonella typhimurium Species: Bacteria

A major challenge in mitigating infectious disease risks during spaceflight is to understand, model, and integrate the combined action of cellular, molecular, and biochemical networks in the host that potentiate transition to disease in response to infection by pathogens cultured in microgravity. This is a critical issue to address, as spaceflight negatively impacts crew immune function and alters microbial virulence, gene expression, and antimicrobial resistance, strongly suggesting an increased risk for in-flight infectious disease. Herein, we propose to apply our 3-D intestinal co-culture models as human surrogates to characterize their transcriptomic (via RNA-Seq), metabolomic (via mass spectrometry), and inflammatory responses to infection with spaceflight analogue and control-cultured Salmonella typhimurium. To facilitate a practical integration of these systems, the combined analysis proposed in this study will focus on the metabolomic subset associated with host oxidative stress, redox, and inflammatory responses. These factors are of key importance in the infection process and may contribute to reported abnormalities and dysfunction in the crews' immune system during flight. We will use systems modeling approaches based on both quantitative gene transcript and biochemical metabolite correlation and all of their known/inferable relationships between genes, proteins, pathways, and biochemistry that will allow us to form new bridges and a general framework for making these linkages between gene expression (RNA-Seq) and biochemical (metabolomic) data. This approach will allow for new insights into relationships between redox functions, oxidative stress, inflammation, and infection that either approach alone would not be able to achieve. By exploring interconnections between these systems over different kinetic timepoints before and after infection, this systematic approach will provide an unparalleled level of sensitivity and resolution of the dynamics of the host response to a microgravity-analogue cultured pathogen, which may lead to identification of novel infection mechanisms and strategies for prevention and control.

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Barrila J, Yang J, Crabbé A, Sarker SF, Liu Y, Ott CM, Nelman-Gonzalez MA, Clemett SJ, Nydam SD, Forsyth RJ, Davis RR, Crucian BE, Quiriarte H, Roland KL, Brenneman K, Sams C, Loscher C, Nickerson CA. Three-dimensional organotypic co-culture model of intestinal epithelial cells and macrophages to study Salmonella enterica colonization patterns. npj Microgravity. 2017 Feb 28;3(1):10. [DOI]

Crabbé A, Liu Y, Sarker SF, Bonenfant NR, Barrila J, Borg ZD, Lee JJ, Weiss DJ, Nickerson CA. Recellularization of decellularized lung scaffolds is enhanced by dynamic suspension culture. PLoS One. 2015 May 11;10(5):e0126846.

Kennedy Ann R., Crucian Brian, Huff Janice L., Klein Sabra L., Morens David, Murasko Donna, Nickerson Cheryl A., and Sonnenfeld Gerald. Journal of Women's Health. November 2014, 23(11): 956-958. [DOI]

Barrila J, Crabbé A, Yang J, Franco K, Nydam SD, Forsyth RJ, Davis RR, Gangaraju S, Ott CM, Coyne CB, Bissell MJ, Nickerson CA. Modeling host-pathogen interactions in the context of the microenvironment: 3-D cell culture comes of age. Infect Immun. 2018 Sep 4. [DOI]

Mission/Study Information
Mission Launch/Start Date Landing/End Date Duration
Ground 05/01/2009 In Progress

Additional Information
Managing NASA Center
Ames Research Center (ARC)
Responsible NASA Representative
Ames Research Center LSDA Level 3
Project Manager: Helen Stewart
Institutional Support
National Aeronautics and Space Administration (NASA)
Proposal Date
Proposal Source
2012 Space Biology NNH12Z