Rosado, Helena Isabel Venâncio; (2009) Effects of simulated microgravity on the virulence properties of the opportunistic bacterial pathogen Staphylococcus aureus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Microbiological monitoring of air and surfaces within the International Space Station (ISS) has indicated that bacteria of the genus Staphylococcus are found with high frequency. Staphylococcus aureus, an opportunistic pathogen with the capacity to cause severe debilitating infection, constitutes a significant proportion of these isolates. Ground-based studies of Salmonella enterica have provided evidence that bacterial virulence is increased under the influence of simulated microgravity. These studies, and others linking space flight to reduced immune competence, provide clear evidence that extended missions may be compromised by increased risk of infection. The effects of simulated microgravity on the virulence properties of S. aureus were therefore examined. The methicillin-susceptible S. aureus (MSSA) isolates RF1, RF6 and RF11 were grown in a Synthecon High Aspect Ratio Vessel (HARV) under low shear modelled microgravity (LSMMG) and compared with cells grown under normal gravity (NO). There were no significant differences in the growth rate, antibiotic susceptibility or cell morphology of MSSA grown under LSMMG compared to NG. Growth in a modelled microgravity environment had an impact on a number of factors associated with the virulence of S. aureus. Pigment production and haemolysin secretion was significantly reduced in all three isolates under LSMMG. Global gene expression was determined by DNA microarray analysis and protein secretion examined using two-dimensional gel electrophoresis. LSMMG elicited large reductions in protein secretion by the three isolates; in particular isolate RF6 displayed a fivefold reduction in protein secretion. In total, 40 proteins were found to be down-regulated under LSMMG in a highly reproducible fashion. LC-MS/MS identified these proteins to be involved mainly with cell metabolism, including protein biosynthesis, folding and transport. DNA microarray identified significant changes in gene regulation; these were in the main associated with cell metabolism, transport, stress and virulence. For isolate RF6, the expression of a major virulence gene, hla, and the virulence regulatory system saeRS was found to be reduced two- and fivefold respectively. These data provide strong evidence that growth of S. aureus under modelled microgravity leads to a reduction in expression of virulence determinants. This observation raises the possibility that pharmacological modulation of the "microgravity trigger" that produces this avirulent phenotype would "disarm" the pathogen and resolve staphylococcal infections. This work constitutes the first step in a search for inhibitors that would prevent the secretion of a family of proteins necessary for infection to take place; the attenuated phenotype generated by such pharmacological intervention would not survive systemically and invading bacteria are likely to be removed by host immune surveillance. In contrast to conventional antibiotics, such therapeutic agents would modify rather than kill the target pathogen and consequently apply less direct selective pressure on bacterial populations.

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