Like a burglar with a universal lock pick, many deadly pathogens use the same protein to gain access to the cells of a potential host, researchers have discovered. The new findings could have implications for blocking infections by agents ranging from wheat rust to malaria.



Pathogenic fungi, such as flax rust and soybean rust, and similar pathogens known as oomycetes, such as the organism behind the Irish potato famine and sudden oak death, make similar proteins to disarm their hosts' defenses. But to work, these effector proteins need to first make their way inside of a cell. And until now, scientists did not know, in the first place, how these compounds were able to break in.



A new study, published online July 22 in Cell describes how these blights do it.



To infect a plant, pathogenic fungi and oomycetes make a protein called RXLR—a type of effector protein—which enters plant host cells and blocks the plant's defenses. But the new research shows that both of these types of organisms are able to insert their effector proteins inside the cell by binding with a single type of lipid on the host cell's surface. This union allows the effector protein to be carried into the cell through the cell wall, where it can start doing damage.



"Even though they're very different, they're using a similar mode of entry," says Shiv Kale, a National Science Foundation graduate research fellow at Virginia Tech's Virginia Bioinformatics Institute and lead author of the new paper, of the various plant pathogens. The "key" that the pathogens use to get into host cells is a lipid known as phosphatidylinositol-3-phosphate (or PI-3-P).



That such different organisms would make use of a single lipid was a surprise to Kale and his colleagues. And although PI-3-P had been described before, "that lipid is predominantly on the inside of the cell," Kale says, so finding it on the exterior surface of the cells was "really exciting."



Even though the universality of the lipid use was unexpected, "it makes sense from an evolutionary standpoint," Kale explains. If the single key could give pathogens access to a multitude of hosts, the talent would be worth keeping around, leading Kale to conclude that the pathogens' mode of entry is probably "ancient and highly conserved." The single common technique for entry could be salutary for humans and the crops we depend on, though, as researchers in agriculture and medicine strive to find the best ways to block fungal and oomycete infections.



"The finding is no doubt a breakthrough in host–pathogen interaction," Takao Kasuga and Lynn Epstein, both of the Department of Plant Sciences at the University of California, Davis, noted in a joint e-mail to ScientificAmerican.com. "We now know how pathogens' effector proteins are delivered into host cells."



These lipid receptors were not just found on the surface of the plant cells tested by Kale and his colleagues, but on some animal cells as well—including human lung epithelial cells.



Kale is hopeful that the findings might someday be put to use in new treatments that could suppress PI-3-P and block the pathogen's path. "It seems that if you can find a target for this entry mechanism, you could develop a therapeutic," he says.



Such a medication might be useful to patients who have compromised immune systems and fall prey to fungal infections that healthier individuals can usually fight off, such as those with AIDS who are more susceptible to cryptococcal meningitis, a fungal infection that can attack the nervous system.



The new data, however, did not illuminate whether any of the host's biological processes would be interrupted if the binding capabilities of their cells' external PI-3-P were inhibited, Kale says.



And not everyone is sure blocking the host's binding lipid is going to be a simple approach. The substance in question is "a ubiquitous and extremely important part of the cell membrane," Kasuga and Epstein noted. "Manipulating and blocking of effector–PI-3-P interactions without interfering with PI-3-P functions in healthy cells may be a challenge."



More broadly, the findings could help to shed light on other scourges, such as malaria. Red blood cells, which malaria infects, have not been shown to have PI-3-P on their surfaces. Nevertheless, the malaria parasite Plasmodium seems to have developed a similar mechanism for entering the cells, Kale notes. And by examining various entry methods of pathogens, researchers like Kale hope to zero in on an early, possibly universal step in the infection process.



Currently, scientists from various disciplines are designing new trials to start putting these findings to work in agricultural and medical realms. Kale notes that this sort of basic discovery, although minute, is just the kind of jumping-off point many basic science researchers dream of. He hopes that eventually preventive treatments will "have some benefit to humanity because of it."