A Hometown Pathogen the Hometown Would Like to Forget—Effector Protein’s Role in Legionella Described in Philadelphia

Ligonella growing on an agar plate shown under UV light. Image credit: CDC/James Gathany

Ligonella growing on an agar plate shown under UV light. Image credit: CDC/James Gathany

Philadelphia is an apt location to give a talk about Legionella pneumophila. The Legionella bacterium was discovered in 1977 after a deadly outbreak of a mystery illness at a Philadelphia meeting of the American Legion at the Bellevue-Stratford Hotel in 1976. Two hundred twenty one of the convention attendees developed flu-like symptoms and 34 later died of pneumonia. The illness, hence named Legionnaires’ disease, was transmitted via the air conditioning system of the hotel. It is still common in developed countries, but how Legionella evades the host’s defenses is still not precisely understood. Matthias Machner, investigator at the NIH Eunice Kennedy Shriver National Institute for Child Health and Human Development, thinks he has a piece of the answer. Machner was in Philadelphia last Sunday at the 2014 ASCB/IFCB meeting to describe how Legionella uses an effector protein called VipD to disable the endo-lysomal pathway by first locating a critical protein, Rab5, and then by snipping a nearby lipid that serves as a signpost for endosome formation

Interviewed in Philadelphia before his talk, Machner said that VipD’s seek-and-snip powers are probably only part of Legionella’s toolkit for host invasion. “I think the fascinating part of studying pathogens is they exploit the [host] cell using many of the cell’s own tools. They are the ultimate cell biologists, you might say.” Machner has been studying Legionella since he was a postdoc at Tufts in Ralph Isberg’s lab. The lab had identified about 20 new proteins that Legionella uses to infect cells and Machner saw a wide-open opportunity to make additional discoveries. “I thought at the time this was a huge number, and they had no idea what these proteins were doing… I thought this was a great chance to work on these proteins and determine their function,” Machner recalled.

“Now almost 10 years later, the number of effectors has increased to almost 300, which gets me even more excited,” he said. “Most of these proteins have not been studied in detail. The few that have been characterized in detail have really fascinating activities.” His latest finding is one of them.

Legionella is an airborne pathogen. It thrives in freshwater environments, natural or manmade. When droplets get aerosolized and inhaled by humans, they enter the lung and can infect macrophages. In the environment, Legionella infects amoeba, its natural host… [Macrophages] are primed to take up all the bacteria we inhale on a daily basis and degrade them in the endo-lysosomal pathway. Legionella has developed tools to escape this endo-lysosomal degradation,” Machner explained. His lab focuses on how Legionella can evade degradation. One of the 300 effector proteins, VipD, Machner discovered, plays a key role.

VipD prevents Legionella degradation by acting on Rab5, a protein critical for the fusion of endosomes. But instead of just turning off Rab5, as Machner had thought, its function is more sophisticated. VipD uses Rab5 just to make sure it’s in the right place. Once at the endosome, VipD clips a key lipid that acts as a signpost for endosomes to a host of other proteins, including those involved in the fusion process. Though Machner thinks it’s likely that there are numerous other proteins that help Legionella infect cells, he said, “We think this is the first molecular mechanism that describes how Legionella can manipulate endosomal function within host cells.”

“We can learn a lot from bacteria, especially Legionella, which has coevolved with amoeba for millions and millions of years and has perfectly adapted to its intracellular environment, so it has figured out the cell. If we understand how Legionella manipulates cells, we can also learn a lot about how our own cells work,” Machner said.

About the Author:

Christina Szalinski is a science writer with a PhD in Cell Biology from the University of Pittsburgh.