Spaceflight offers a unique platform to explore fundamental questions about human health and disease and represents a paradigm shift in how we study cellular responses to extreme conditions. The key to this research is the novel way that cells respond to spaceflight, as they exhibit biological changes that are directly relevant to human health that are not observed using traditional experimental approaches. We discovered that a) spaceflight alters the virulence and gene expression of the bacterial pathogen Salmonella, and that the highly conserved RNA-binding protein Hfq plays a central role in regulating this response, and b) these conditions regulate Hfq in other bacterial pathogens. Interestingly, mammalian cells contain structural and functional homologues of Hfq, the Sm proteins - a family of evolutionarily conserved RNA-binding proteins which play key roles in cellular responses to stress, differentiation and function of human cells/tissues, immune system function, and tumorigenesis. This proposal aims to identify common conserved cellular and molecular spaceflight response mechanisms in human cells relevant to normal cellular function and disease progression by profiling expression levels of Sm proteins, changes in cellular differentiation, immune function and stress responses before-and-after pathogen challenge. If Sm proteins serve as spaceflight response regulators (as we propose is the case for their prokaryotic Hfq homologues) this work would translate into knowledge of host response to infection and larger physiological stress responses relevant to cellular homeostasis and disease development. The implications of a universally conserved molecular response to spaceflight across a variety of cell types proposed in this first-of-its-kind study would affect NASAs approach to infectious disease and immunological risk assessment - and would be first to profile the infection process in human cells during spaceflight, representing a major advance in understanding the spaceflight effect on host-pathogen interaction dynamics, resistance to infection, immune function, and risk of in-flight disease.
Understanding infectious disease risks during spaceflight is critical to provide safe passage for human exploration to the moon and Mars. This issue is especially important given reports that the crews immune system is dysfunctional during flight (86, 95); and our recent landmark discovery that spaceflight increased the disease-causing potential (virulence) and globally altered the gene expression of the human pathogen Salmonella typhimurium ((104); Wilson et al., 2008 - Submitted). These flight experiments confirmed our earlier findings that ground-based spaceflight analogue culture, designated as low shear modeled microgravity (LSMMG), globally altered Salmonellas gene expression profiles and increased its virulence (62, 64). Consistent with increased virulence, LSMMG cultured Salmonella also exhibited important changes in virulence-related stress responses, like increased resistance to acid stress and enhanced intracellular survival in macrophages (64). In our efforts to determine the mechanism(s) behind these spaceflight and LSMMG-induced responses in Salmonella, we discovered that a) the Hfq protein serves as a master/central molecular regulator of many of these responses - including the LSMMG-induced acid stress response, and the LSMMG and spaceflight-induced stimulons - including small non-coding regulatory RNAs (small RNAs) ((104); Wilson et al., 2008 - Submitted); and b) environmental ion concentrations mitigated the enhanced virulence observed in spaceflight-grown Salmonella, and also altered its LSMMG-induced acid stress response (Wilson et al., 2008 - Submitted). Hfq is a highly conserved bacterial RNA chaperone protein that binds to small RNAs thereby facilitating their association with mRNAs, the result of which plays a diverse role in prokaryotic gene expression (including regulation of ion response pathways), virulence, and physiology in response to stress (28, 29, 31, 49, 68, 84, 85). In addition, our preliminary data analysis of spaceflight cultures of P. aeruginosa have provided evidence that spaceflight also alters the hfq regulon in this organism (Unpublished data).
|Effective start/end date||5/1/09 → 4/30/13|
- NASA: Ames Research Center: $396,600.00