July 23, 2010 A research team led by scientists at the Virginia Bioinformatics Institute (VBI) at Virginia Tech has discovered a fundamental entry mechanism that allows dangerous fungal microbes to infect plants and cause disease. The discovery paves the way for the development of new intervention strategies to protect plant, and even some animal cells, from deadly fungal infections.
The findings are published in the July 23 edition of the journal Cell.
The researchers have revealed how special disease-related proteins, known as effectors, blaze a trail into cells. Fungi and fungal-like microbes known as oomycetes produce effector molecules that penetrate cells and switch off the host's defense system. Once the host's immune system has been disabled, the fungus or oomycete swiftly follows up, breaking and entering the cell and unleashing disease.
The pathogens in question, which include the microbe that caused the Irish potato famine in the nineteenth century, cause billions of dollars of losses for commercial farmers worldwide in crops such as soybean. They are also responsible for potentially fatal infectious diseases in humans.
Said Brett Tyler, professor at VBI and the leader of the project, "Our breakthrough finding is that these dangerous disease-causing proteins must bind a specific lipid molecule found on the cell surface before they can enter the cell."
In a previous study, Tyler and other researchers had pinpointed specific regions of the effector proteins that are intimately involved in breaking and entry of the cell. The new study shows that these regions on the effector proteins bind the lipid phosphatidylinositol 3-phosphate and that this binding is essential for the proteins to enter the cells. Adds Tyler, "The nasty proteins enter by hitching a ride on a lipid raft, a region of the cell's outer membrane that can be internalized by the cell. The lipid acts as a bridge between the effector protein and the raft, and in doing so help to unlock the door for entry of the disease-causing proteins into the cell."
Intriguingly, the researchers have also identified two methods to block the entry process that could lead to new disease interventions against infection in medicine and agriculture. Shiv Kale, a graduate student at VBI and one of the lead authors on the study, remarked: "We were able to block the entry process of the disease-related proteins using two types of inhibitors. The first group of inhibitors covers the lipid so that the pathogen cannot get access to it. The second jams the site on the protein that normally binds the lipid."
The scientists were also able to show that the entry process into some human cells takes place by the same mechanism. Said VBI Associate Professor Chris Lawrence, who collaborated on the study, "Our finding that the entry of the effectors into human cells can be blocked with small molecules suggest that it may be possible to find new strategies to combat several debilitating human diseases, in addition to treating plant diseases."
It was previously known that some bacteria, fungi and oomycetes infect plants by slipping effectors that disable immune systems into plant cells. But only the mechanism used by bacteria to insert their effectors into host cells had been previously identified: bacteria puncture the host cell's membrane and then inject their effectors into the host cell's membrane with a needle-like structure. By contrast, the mechanism used by fungi and oomycetes--neither of which have an injection apparatus--to slip their effectors into plant cells had not been previously identified before.
Also, the binding lipid used by the effectors of fungi and oomycetes had never before been detected on cell surfaces (although it had been detected inside cells). So the Tyler team's discovery of the presence of this binding lipid on cell surfaces and the ability of the microbial effectors to use it to invade cells were both surprising.
Also surprising were:
- The novelty and simplicity of the mechanism used by fungi and oomycetes to insert their effectors into host cells.
- The discovery that fungi and oomycetes use the same binding mechanism to introduce effectors into plant cells, even though these two classes of microbes are evolutionarily distinct from one another.
- The presence of an abundance of the binding lipids on the surfaces of plant cells, animal cells, and some human cells. This discovery suggests that fungal and oomycete effectors might also enter animal and human cells through the same newly-discovered method they use to enter plants. It also suggests that this phenomenon may, in fact, be an attack mechanism common to fungal and oomycete diseases of plants, animals and humans.
The research was funded by the National Science Foundation and by United States Department of Agriculture's National Institute of Food and Agriculture.
The team of researchers included Associate Professor Christopher Lawrence of the VBI, Assistant Professor Daniel Capelluto of the Department of Biological Sciences at Virginia Tech, and Professor Weixing Shan of China's Northwest Agricultural and Forestry University.
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- Kale S, Gu B, Capelluto DGS, Dou D, Feldman E, Rumore A, Arredondo FD, Hanlon R, Fudal I, Rouxel T, Lawrence CB, Shan W, Tyler BM. External lipid phophatidylinositol 3-phosphate mediates entry of eukaryotic pathogen effectors into plant and animal host cells. Cell, 2010; DOI: 10.1016/j.cell.2010.06.008
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