Duke University Medical Center microbiologists have discovered that the parasitic bacteria Chlamydia escapes cellular detection and destruction by cloaking itself in droplets of fat within the cell. The researchers said that their findings represent the first example of a bacterial pathogen "mimicking" such a structure, or organelle, within a cell.
Not only do the findings suggest a novel mechanism of bacterial infection, but the new insights into Chlamydia's actions within infected cells provide rational targets for potential drugs to halt the spread of the bacteria, said the researchers. Chlamydia has been implicated in sexually transmitted infections, atherosclerosis and some forms of pneumonia.
Chlamydia is an obligate intracellular parasite that prospers within a host cell by hijacking the cell's internal machinery to survive and replicate. The bacterium lives within the cell in a protective capsule known as an inclusion. To date, it has not been clearly understood how Chlamydia has evolved to evade the cell's internal intruder alert system.
"In our experiments, we found that Chlamydia recruits lipid droplets from within the cell and stimulates the production of new droplets, which cover the surface of the inclusion," explained Yadunanda Kumar, Ph.D., a post-doctoral fellow in Duke's Department of Molecular Genetics and Microbiology. "This action of surrounding itself with lipid droplets may represent an example of organelle mimicry, where the chlamydial inclusion is protected from the cell's defenses by being perceived by the cell as just another lipid droplet."
Kumar presented the results of the Duke research Dec. 11, 2005, at the 45th annual meeting of the American Society for Cell Biology in San Francisco. The research was supported by National Institutes of Health, the Pew Foundation and the Whitehead Foundation.
When these cloaked inclusions were treated with agents known to inhibit the production of lipid droplets, the researchers were able to significantly reduce the ability of the bacterium to replicate.
"It has long been thought that lipid droplets within cells were just passive repositories of energy for the cells," said Duke microbiologist Raphael Valdivia, Ph.D., senior member of the research team. "But now we are learning that these structures appear to play important roles in lipid synthesis and transport of cholesterol throughout the cell, and cell signaling."
For their experiments, the researchers studied Chlamydia trachomatis, which is spread in humans by sexual contact and can lead to such disorders urinary tract infections, eye infections and arthritis.
Because the bacterium is an obligate parasite, researchers cannot directly manipulate its genes. So the Duke team removed genetic material from the bacterium and inserted them into yeast cells, which share many common structures and features with human cells.
When the researchers screened the chlamydial proteins in yeast cells, they found four specific proteins that appeared to recruit and spur the production of lipid droplets.
"Our findings provide evidence for a novel mechanism of organelle subversion where Chlamydia recruits lipid bodies and co-opts their function for survival," Valdivia said. "Chlamydia may exploit lipid droplets to acquire lipids, modulate inflammation or just for protection."
If unchecked, the inclusion will continue to grow until it fills the entire cell, causing it to explode, releasing thousands of bacteria ready to infect adjacent cells.
The findings also open the possibility of interfering with Chlamydia's ability to infect cells by disrupting the biosynthesis neutral lipids and lipid droplets. Further research will be needed to develop such treatments, since the agent the researchers used to inhibit lipid synthesis in the laboratory is not a drug that is used clinically in humans.
The researchers believe that the same process may be involved in other species of Chlamydia since the genetic make-up of these bacteria has changed little over the hundreds of millions of years of its successful ability to infect eukaryotic cells.
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