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Microgravity Boosts Microbe's Virulence

Unique low fluid-shear forces that 3-D bacterial cultures encounter in space are similar to what pathogens encounter in our bodies. NASA funded work shows that microgravity enhances the disease-causing potential of a bacteria that is responsible for millions of cases of gastrointestinal illness every year. Researchers are identifying the gene activity behind this increased virulence, and laying the scientific foundations for the development of new ways to treat and prevent costly Salmonella infections.

Most people know that a weakened immune system increases an individual's vulnerability to an infectious disease, but bacteria can change their ability to infect as well. "The ability of a microbe to cause disease depends on the microbe's virulence as well as the immune status of the host," says Cheryl A. Nickerson, Ph.D., a partially NASA funded microbiologist in the Biodesign Institute at Arizona State University in Tempe. Nickerson has focused for a decade on how space travel could change the interaction between microbe and host. Published studies now show that space flight or a "bioreactor" that simulates the low gravity of space flight can increase the potential of microbes to produce disease.

Two to four million cases of Salmonella-induced gastrointestinal illness each year in the United States usually resolve themselves without medical attention. But the microbe is potentially fatal in people with weakened immune systems. "Something like food poisoning could disrupt a space mission, at a cost of millions of dollars, or - even worse - threaten crew survival," says Nickerson.

Microbes Fly Aboard the Space Shuttle

When Space Shuttle Endeavor lifted off in March 2008, it contained Nickerson's payload of Salmonella, among other common Earth pathogens, in an experiment designed to build on her team's emerging knowledge about how infection works and how to counter it both in space flight and on the ground. On a prior shuttle flight in September 2006 on Atlantis, her team showed that microgravity changed the pattern of gene activation in Salmonella. They found that Salmonella colonies had different activity (expression) for 167 genes, as compared to the same bacteria grown in identical conditions on Earth at normal gravity. Colonies grown in space were also nearly three times more likely to produce illness when introduced into ground-based mice. The research team then sought to confirm and extend these results in an independent experiment on Endeavor in March 2008.

In a recent statement to the House Science and Technology Committee, Nickerson mentioned that their first flight identified a "master switch" that controls Salmonella responses to space travel. Her team determined that production changed for 73 proteins. They identified a RNA-binding protein, called Hfq, as a likely global regulator involved in this response to the low gravity environment, as published in Proceedings of the National Academy of Sciences. "This molecular target (Hfq), and others that we identified, hold the potential to be translated into new therapeutic and vaccine approaches," Nickerson told the Committee. The shuttle-flown Salmonella also behaved as if they were forming a biofilm, which helps bacteria to resist attack by the immune system and by antibiotics. The matching microbes grown on the ground gave no signs of biofilm formation.

Nickerson indicates that current evidence suggests that the unique low fluid-shear forces that bacteria encounter in space are similar to what pathogens encounter in our bodies. There may be a common regulatory theme governing these microbial responses, but to prove that, scientists needed to fly different bacteria together on the same flight so that all could be tested under the same conditions. This took place on the 2008 mission, and the results will be submitted for publication when available.

Based on earlier ground studies, the latest experiments changed the concentration of ions, the charged salt particles present in body fluids, to see if this could counter or stop the increased infectivity observed for microbial cultures during space flight. Other teams of investigator,s with payloads on the flight, tested gene activation and virulence of different disease-producing microorganisms, including Streptococcus pneumoniae and Pseudomonas aeruginosa.

Work on the Ground

These Shuttle experiments were based on ground-based studies using a "bioreactor" 3-D cell culture system known as a Rotating Wall Vessel, which simulates some aspects of space flight. The bioreactor is a hollow cylinder completely filled with culture media and cells. When the bioreactor rotates, the cells are kept in a condition similar to the free fall experienced by shuttle astronauts around the Earth. The fluid that cells grow in flows at low speed past their cell surfaces. This low fluid-shear force mimics the fluid flow environment that the bacteria experience in certain regions of the human body that they are able to infect, such as the lining of the intestines. The microbes sense the flow of fluid past their surfaces, and signal that information to their genes. They then make the proteins best suited to the current environment to allow the microbes to survive and thrive.

Indeed, the bacteria growing within the rotating bioreactor show significant differences in physiology and patterns of gene activation. Moreover, mice infected with microbes cultured in a bioreactor died an average of three days earlier, using less bacteria, than the control mice infected with the same type of bacteria cultured in conventional 2-D cultures. The investigators found larger numbers of the bioreactor-grown microbes in the livers and spleens of the experimental mice.

All these findings converge to indicate that an environment of low fluid-shear alters the disease producing potential of Salmonella in ways that could not be identified using traditional experimental approaches. The results from Nickerson and her team offer new insight into how this pathogen causes disease and thus for the development of new strategies to combat human illness caused by Salmonella.

Nickerson emphasizes that space flight remains a crucial part of investigating the virulence of microbes in space. The bioreactor only replicates some aspects of microgravity. "To remove or greatly reduce gravity is an enabling platform that only spaceflight can provide and one which will uncover new ways to mitigate the risk of infectious disease to the space crew," Nickerson says, "and can be translated into innovative drugs, therapeutics and vaccines" to keep us healthy on Earth.

1. Spaceflight alters bacterial gene expression and virulence and reveals role for global regulator Hfq. Proc. Natl. Acad. Sci. USA. Sep 2007, 104(41):16299-304.
2. First Report of In Vitro Infection of a 3-Dimensional Organoid Model of Human Small Intestinal Epithelium with Human Noroviruses. Emerging Infectious Diseases. Mar 2007, 13(3):396-403.
3. Studying host-pathogen interactions in 3-D: Organotypic models for infectious disease and drug development. Journal of Neuroimmune Pharmacology. Mar 2007, 2(1):26-31.

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