Study Reveals a Secret to the Success of Disease-Causing Microbes: discovery may generate new strategies to fight serious human diseases

Oomycetes and fungi infect plant, animal and sometimes even human cells by secreting a protein called an effector protein into the spaces between the host's cells. This secreted effector binds to a lipid raft on the surface of a host cell and rides the raft into the cell. Once inside the cell, the invading effector disables the host's immune system. Image by Zina Deretsky, National Science Foundation

A study published in the July 23 issue of Cell identifies the mechanism used by several types of common, virulent microbes to infect plants and cause devastating blights. Microbes using this infection mechanism include fungi that are currently causing wheat rust epidemics in Africa and Asia, and a class of parasitic algae, called oomycetes, that resulted in the Irish potato blight of the 19th Century. These microbes remain an agricultural scourge today.

The researchers also found evidence suggesting that fungi and oomycetes might infect humans and animals through the same newly-discovered mechanism as they use to infect plants. Human diseases caused by fungi include valley fever and several infections common to AIDS patients. In addition, in water environments, oomycetes cause destructive diseases in people and animals. For example, they attack the legs, eyes and brains of rice farmers in Southeast Asia, and they destroy spawning salmon.

"Our findings suggest broad new strategies for combating the most damaging diseases of the world's major food crops, including wheat, rice, maize and potatoes, as well as several nasty human diseases," said Brett Tyler of the Virginia Bioinformatics Institute at Virginia Polytechnic Institute, Blacksburg, Va.--the leader of the study.

The infection mechanism

According to the Tyler team's study--which was funded by the National Science Foundation and the United States Department of Agriculture's National Institute of Food and Agriculture--once a fungus or an oomycete comes into contact with a host, it may initiate an infection by secreting a special protein, called an effector, into spaces between the host's cells. (See illustration.) Each fungal and oomycete effector consists of a long chain of amino acids. Most of this chain is designed to disable a host cell's immune system. However, a small stretch of it, which contains four particular amino acids, binds to a specific type of lipid; this lipid is a fat-like molecule that is part of the membrane surrounding the host cell.

After the effector is secreted, its binding section attaches to the binding lipid on the surface of a host cell, like the "lipid raft" shown in the illustration. Like a key that opens a locked door to an invader, the resulting effector-lipid connection unlocks the host cell to the invading effector. Once unlocked, the cell extends itself to engulf and absorb the effector. (This process is called endocytosis.)

After entering the host cell, the invading effector disables the host cell's immune system by destroying or jamming key components of its immune system's machinery. Unrestrained by the host's damaged immune system, the infecting fungus or oomycete is free to spread unchecked throughout the host's tissues.

What's so surprising?

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.

Implications for future therapies

The Tyler team's findings also demonstrated that it is possible to block fungi and oomycete effectors from entering host cells by preventing them from attaching to binding lipids. This finding opens new potential avenues for developing therapies for fighting diseases caused by fungi and oomycetes.

Tyler's team included Christopher Lawrence of the Virginia Bioinformatics Institute at Virginia Polytechnic Institute; Daniel Capelluto of Virginia Polytechnic Institute; and Weixing Shan of China's Northwest Agricultural and Forestry University.

In addition, the paper's lead author was Shiv Kal--Tyler's graduate student; he was supported while conducting this research by a National Science Foundation predoctoral fellowship. Kale remarked, "This is a great example of transdisciplinary research, pulling together researchers from around the world with expertise in oomycetes, fungi, human disease and lipid chemistry."

This news is from the National Science Foundation,  July 22, 2010.