Microgravity Stress Alters Bacterial Virulence
Studies have shown an increase in the virulence, changes in growth modulation and alterations in response to antibiotics in certain bacteria both in space and simulated microgravity.[15–19] Significant technological and logistical hurdles have hindered thorough genotypic and phenotypic analyses of bacterial response to actual space environment. In this line, Wilson et al. cultured Salmonella enterica Typhimurium aboard space shuttle mission STS-115 with identical cultures as ground controls. Global microarray and proteomic analyses were carried out and 167 differentially expressed transcripts and 73 proteins were identified among which conserved RNA-binding protein Hfq was suggested as a likely global regulator involved in the response to spaceflight. Similar results were obtained with ground-based microgravity culture model. Furthermore, spaceflight-grown S. enterica Typhimurium had enhanced virulence in murine models and exhibited extracellular matrix accumulation consistent with a biofilm.
S. Typhimurium grown in spaceflight analog exhibited increased virulence, increased resistance to environmental stresses (acid, osmotic and thermal stress), increased survival in macrophages and global changes in gene expression.[20–22] Low-shear modeled microgravity rendered adherent–invasive Escherichia coli more adherent to a mammalian gastrointestinal epithelial-like cell line, Caco-2. Simulated microgravity conditions markedly increased production of the heat-labile enterotoxin from enterotoxigenic E. coli. Upon a 12-day exposure to low-shear modeled microgravity, Candida albicans exhibited increased filamentation, formation of biofilm communities, phenotypic switching and more resistance to the antifungal agent amphotericin B.
Only one virulence gene was found among 163 differentially expressed genes in simulated microgravity grown S. Typhimurium and actually, most virulence genes were expressed at a lower level (including genes involved in lipopolysaccharide production). Furthermore, sigma factor (a transcription factor responsible for a general stress response) was not thought to be a cause, since a decreased level of its gene expression was observed in simulated microgravity. The mechanism of enhanced virulence of S. Typhimurium grown in actual spaceflight and rotating wall vessel culture conditions does not involve an increased expression of traditional genes that regulate the virulence of this bacterium under normal gravity conditions; however, Hfq pathway is required for full virulence in S. Typhimurium.
Biofilm formation is part of the normal growth cycle of most bacteria and this film is linked to chronic diseases that are difficult to treat such as endocarditis, cystitis and bacterial otitis media. Bacterial biofilm creates superior resistance to oxidative, osmolarity, pH and antibiotic stresses. Theoretically, bacterial biofilm production, which enhances bacterial survival by resistance to the immune system and antimicrobial agents, may increase the risk and/or severity of infection in long-term space missions. Diminished gravity has been shown to stimulate bacterial biofilm formation both in E. coli and Pseudomonas aeruginosa.[30–32] In a study by Crabbe et al. in 2008, rotating wall vessel technology was exploited to study the effect of microgravity on growth behavior of P. aeruginosa PAO1. Rotating wall vessel cultivation resulted in a self-aggregating phenotype which subsequently led to formation of biofilms. In a second study in 2010, the same researchers employed microarrays to investigate the response of P. aeruginosa PAO1 to low-shear modeled microgravity both in rotating wall vessel and random position machine.P. aeruginosa demonstrated increased alginate production and upregulation of AlgU-controlled transcripts (including those coding for stress-related proteins) in modeled microgravity. Results of the study also implicated the involvement of Hfq in response of P. aeruginosa to simulated microgravity. Involvement of Hfq in response of P. aeruginosa to actual spaceflight was later confirmed in another study.
In addition, there is concern that antibiotic-resistance increases during short-term spaceflight. The MIC of both colistin and kanamycin increased significantly in E. coli grown aboard the flight module compared with the MIC on the ground. A similar increase in the MIC of oxacillin, erythromycin and chloramphenicol was reported in Staphylococcus aureus.[34,35] This has led to concerns that the efficacy of antibiotics may be diminished during even short orbital missions.[36,37]
It has been hypothesized that reduction in the natural, terrestrial diversity of the gastrointestinal bacterial microflora in spaceflight may give rise to an increase in the presence of the drug-resistant bacteria. It has also been postulated that the emergence of such resistant clones could be facilitated by the administration of antibiotics either before or during the flight. Emergence of drug resistance is also facilitated by bacterial mutation which occurs more frequently in long-term spaceflights. Overall, there is the possibility that drug-resistant bacteria could colonize all crew members on a mission, giving rise to a difficult-to-treat healthcare problem.
Future Microbiol. 2012;7(9):1037-1046. © 2012 Future Medicine Ltd.