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Asparagine biosynthesis as a mechanism of increased host lethality induced by Serratia marcescens in simulated
Rachel Gilbert1, Nicole Tanenbaum2, Sharmila Bhattacharya3
1NASA Postdoctoral Program, Universities Space Research Association, NASA Ames Research Center, Moffett Field, CA, USA.
Abstract:
While studies have shown an increase in pathogenicity in several microbes during spaceflight and after exposure to simulated microgravity, the mechanisms underlying these changes in phenotype are not understood across different pathogens, particularly in opportunistic pathogens. This study evaluates the mechanism for increased virulence of the opportunistic gram-negative bacterium, Serratia marcescens, in simulated microgravity. Low-shear modeled microgravity (LSMMG) is used in ground-based studies to simulate the effects of microgravity as experienced in spaceflight. Our previous findings showed that there was a significant increase in mortality rates of the Drosophila melanogaster host when infected with either spaceflight or LSMMG treated S. marcescens. Here, we report that LSMMG increases asparagine uptake and synthesis in S. marcescens and that the increased host lethality induced by LSMMG bacteria grown in rich media can be recapitulated in minimal media by adding only aspartate and glutamine, the substrates of asparagine biosynthesis. Interestingly, increased bacterial growth rate alone is not sufficient to contribute to maximal host lethality, since the addition of aspartate to minimal media caused an LSMMG-specific increase in bacterial growth rate that is comparable to that induced by the combination of aspartate and glutamine, but this increase in growth does not cause an equivalent rate of host mortality. However, the addition of both aspartate and glutamine cause both an increase in host mortality and an overexpression of asparagine pathway genes in a LSMMG-dependent manner. We also report that L-asparaginase-mediated breakdown of asparagine is an effective countermeasure for the increased host mortality caused by LSMMG-treated bacteria. This investigation underscores the importance of the asparagine utilization pathway by helping uncover molecular mechanisms that underlie increased mortality rates of a model host infected with microgravity-treated S. marcescens and provides a potential mitigation strategy.
Insights
Simulated microgravity increases Serratia marcescens virulence by boosting asparagine synthesis. This leads to higher host mortality, but L-asparaginase can counteract this effect, offering a potential mitigation strategy.
Area of Science:
- Microbiology and Space Biology
- Pathogen Virulence Mechanisms
- Host-Pathogen Interactions
Background:
- Increased microbial pathogenicity during spaceflight and simulated microgravity is observed, but underlying mechanisms remain unclear, especially for opportunistic pathogens.
- Previous studies indicated higher mortality rates in Drosophila melanogaster infected with spaceflight or low-shear modeled microgravity (LSMMG)-treated Serratia marcescens.
- Understanding these virulence changes is crucial for astronaut health and microbial risk assessment in space environments.
Purpose of the Study:
- To investigate the molecular mechanisms behind the increased virulence of Serratia marcescens under simulated microgravity conditions.
- To identify specific metabolic pathways and substrates contributing to enhanced pathogenicity.
- To explore potential countermeasures against microgravity-induced bacterial hypervirulence.
Main Methods:
- Utilized low-shear modeled microgravity (LSMMG) to simulate spaceflight conditions on Serratia marcescens.
- Grew bacteria in rich and minimal media supplemented with specific amino acids (aspartate, glutamine) to assess metabolic contributions.
- Quantified host mortality rates in Drosophila melanogaster and analyzed gene expression of the asparagine utilization pathway.
- Tested the efficacy of L-asparaginase as a countermeasure against LSMMG-induced hypervirulence.
Main Results:
- LSMMG significantly increases asparagine uptake and synthesis in Serratia marcescens.
- Supplementation with aspartate and glutamine in minimal media recapitulated the increased host lethality observed in LSMMG-grown bacteria.
- Increased bacterial growth rate alone did not fully account for maximal host lethality; asparagine pathway gene overexpression was LSMMG-dependent.
- L-asparaginase effectively reduced host mortality caused by LSMMG-treated bacteria.
Conclusions:
- The asparagine utilization pathway is a key factor in the enhanced virulence of Serratia marcescens under simulated microgravity.
- LSMMG induces specific metabolic changes, including increased asparagine synthesis, leading to greater host mortality.
- L-asparaginase presents a viable countermeasure to mitigate the increased pathogenicity of microgravity-exposed Serratia marcescens.
