Changes that occur to both the host immune system and pathogenesis of microbes during space flight could represent a formidable challenge to the successful transition from short-to-long-duration space flight. This is a critical issue to address for several reasons, since a) in-flight infections could potentially pose serious risks to the health, safety, and performance of the flight crew, b) studies have indicated that space flight negatively impacts the immune system in both humans and animals, and c) culture of the ubiquitous human bacterial pathogen, Salmonella typhimurium
, under conditions simulating aspects of space flight has been shown to increase the disease causing property of this organism.
Microbiological risks associated with space flight are expected to increase with the length of mission duration. However, the effect(s) of microgravity on the risk of infectious disease events during space flight is not well characterized. In particular, no information is available regarding the ability of microgravity to alter the dynamics of the host-pathogen interaction which leads to infection. Moreover, the biological importance of the immunological changes induced by space flight with regard to resistance to infection remains to be established. A significant application of this research is that by investigating host susceptibility to infection when both the host and pathogen are exposed to microgravity analogues means that mechanistic effects of space flight on host resistance to infection can perhaps be identified.
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The proposed work examined the effect of modeled microgravity (MMG) on the interactions between host (3-D models of human cell cultures) and relevant pathogens (bacterial and viral) when both are simultaneously exposed to this environmental condition. Endpoints to be assayed include adherence, invasion, and intracellular survival profiles, tissue pathology, innate immune responses, and select genomic/proteomic responses of the infected host. The results generated during the course of the proposed studies provided important insight into the effect of space flight on host resistance to infection, and the risk of in-flight infectious disease to ensure crew health and safety.
This project used a unique ground-based model of infection wherein both the host and pathogen are exposed to microgravity analogues to investigate the mechanistic effect of space flight on host resistance to infection.
Appropriately simulating the 3-D environment in which organs and tissues normally function is necessary for development of cultures that realistically resemble in vivo tissues and organs. At the same time, it is essential to accommodate experimental flexibility and high throughput analysis. For these reasons, the availability of reliable, reproducible 3-D tissue assemblies that effectively model the structure and function of human tissues holds tremendous promise for infectious disease research. The investigator used innovative bioengineering technology developed by NASA to establish biologically meaningful 3-D models of human tissues that recapitulate many aspects of the differentiated structure and function of the parental tissue in vivo. The models were applied to study infectious disease caused by a variety of microbial pathogens (bacterial and viral). As a result, a variety of different 3-D models have been established that have been/are being used in infection studies - including small intestine, colon, lung, placenta, bladder, periodontal ligament, vaginal and neuronal models. Published work from the investigators has shown that the 3-D models respond to infection with bacterial and viral pathogens in ways that reflect the infection process in vivo.
The establishment and characterization of biologically meaningful 3-D cultures of human cells and tissues and their practical application in modeling infectious disease provide specific examples of how the study of bacterial and viral pathogenesis can benefit from an appropriate, biologically meaningful 3-D tissue model. In addition, the physiological relevance of the 3-D cell culture models continues to be enhanced by developing multicellular 3-D co-culture models. Thus, in the hierarchical tissue modeling approaches, both the 3-D architecture and multicellular complexity that is inherent in functional tissues in vivo is recapitulated. These physiologically relevant model systems are reproducible, experimentally flexible, cost effective, and offer high throughput platforms that hold promise for the translational advancement of human health.
The work with the 3-D model systems established and funded by this grant and their subsequent application to infectious disease studies has facilitated meaningful dissection of molecular mechanisms of infectious disease caused by bacterial and viral pathogens, including the identity of novel host biosignatures in response to infection (including Salmonella sp, Norwalk virus, and Pseudomonas aeruginosa). It has also allowed the study of infectious disease agents that lack suitable cell culture and animal models (e.g. Norwalk virus). Finally, it has shown exciting potential for the development of novel diagnostics, vaccines, and therapeutic strategies for prevention and treatment.
Barrila J, Radtke AL, Crabbé A, Sarker SF, Herbst-Kralovetz MM, Ott CM, Nickerson CA. Organotypic 3D cell culture models: using the rotating wall vessel to study host-pathogen interactions. Nat Rev Microbiol.
2010 Nov;8(11):791-801. [
Crabbé A, Sarker SF, Van Houdt R, Ott CM, Leys N, Cornelis P, Nickerson CA. Alveolar epithelium protects macrophages from quorum sensing-induced cytotoxicity in a three-dimensional co-culture model. Cell Microbiol.
2010 Nov 5.
Crabbé A, Schurr MJ, Monsieurs P, Morici L, Schurr J, Wilson JW, Ott CM, Tsaprailis G, Pierson DL, Stefanyshyn-Piper H, Nickerson CA. Transcriptional and proteomic response of Pseudomonas aeruginosa PAO1 to spaceflight conditions involves Hfq regulation and reveals a role for oxygen. Appl Environ Microbiol.
2010 Dec 17.
Hjelm BE, Berta AN, Nickerson CA, Arntzen CJ, Herbst-Kralovetz MM. Development and characterization of a three-dimensional organotypic human vaginal epithelial cell model.
2010 Mar;82(3):617-27. Epub 2009 Dec 9. [
Nickerson CA, Richter EG, Ott CM. Studying host-pathogen interactions in 3-D: organotypic models for infectious disease and drug development. J Neuroimmune Pharmacol.
2007 Mar;2(1):26-31. Review. Mar-2007. [
Radtke AL, Wilson JW, Sarker S, Nickerson CA. Analysis of interactions of Salmonella type three secretion mutants with 3-D intestinal epithelial cells. PLoS One.
2010 Dec 29;5(12):e15750. [
Skardal A, Sarker SF, Crabbé A, Nickerson CA, Prestwich GD. The generation of 3-D tissue models based on hyaluronan hydrogel-coated microcarriers within a rotating wall vessel bioreactor. Biomaterials.
2010 Nov;31(32):8426-35. Epub 2010 Aug 7.[
Carterson AJ, Höner zu Bentrup K, Ott CM, Clarke MS, Pierson DL, Vanderburg CR, Buchanan KL, Nickerson CA, Schurr MJ. A549 lung epithelial cells grown as three-dimensional aggregates: alternative tissue culture model for Pseudomonas aeruginosa pathogenesis. Infect Immun.
Crabbé A, Pycke B, Van Houdt R, Monsieurs P, Nickerson C, Leys N, Cornelis P. Response of Pseudomonas aeruginosa PAO1 to low shear modelled microgravity involves AlgU regulation. Environ Microbiol.
Höner zu Bentrup K, Ramamurthy R, Ott CM, Emami K, Nelman-Gonzalez M, Wilson JW, Richter EG, Goodwin TJ, Alexander JS, Pierson DL, Pellis N, Buchanan KL, Nickerson CA. Three-dimensional organotypic models of human colonic epithelium to study the early stages of enteric salmonellosis. Microbes Infect.
LaMarca HL, Ott CM, Höner Zu Bentrup K, Leblanc CL, Pierson DL, Nelson AB, Scandurro AB, Whitley GS, Nickerson CA, Morris CA. Three-dimensional growth of extravillous cytotrophoblasts promotes differentiation and invasion. Placenta.
Myers TA, Nickerson CA, Kaushal D, Ott CM, Höner zu Bentrup K, Ramamurthy R, Nelman-Gonzalez M, Pierson DL, Philipp MT. Closing the phenotypic gap between transformed neuronal cell lines in culture and untransformed neurons. J Neurosci Methods.
2008 Sep 15;174(1):31-41.
Nickerson CA, Honer zu Bentrup K, Ott CM. Three-dimensional cell culture models for drug discovery and infectious disease. Bioforum Europe. 2005 Nov;6:34-6. , Nov-2005.
Straub TM, Höner zu Bentrup K, Orosz-Coghlan P, Dohnalkova A, Mayer BK, Bartholomew RA, Valdez CO, Bruckner-Lea CJ, Gerba CP, Abbaszadegan M, Nickerson CA. In vitro cell culture infectivity assay for human noroviruses. Emerg Infect Dis.
Crew health and performance is critical to successful human exploration beyond low Earth orbit.
The Human Research Program (HRP) investigates and mitigates the highest risks to human health
and performance, providing essential countermeasures and technologies for human space exploration.
Risks include physiological and performance effects from hazards such as radiation, altered gravity,
and hostile environments, as well as unique challenges in medical support, human factors,
and behavioral health support. The HRP utilizes an Integrated Research Plan (IRP) to identify
the approach and research activities planned to address these risks, which are assigned to specific
Elements within the program. The Human Research Roadmap is the web-based tool for communicating the IRP content.
The Human Research Roadmap is located at: https://humanresearchroadmap.nasa.gov/
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for information of how this experiment is contributing to the HRP's path for risk reduction.