The multi-layered success strategy behind this ingenious pathogen is beginning to unfold.

Inside a mouse macrophage, Legionella pneumophila (red) hides in a membrane sac surrounded by regulatory protein Rab1 (green).

To set up house in a host cell, the bacteria responsible for Legionnaires' disease take an aggressive tack—they hijack the host's intracellular trafficking system and build themselves cozy hideouts.

Matthias P. Machner, a research associate in the lab of HHMI investigator Ralph R. Isberg at Tufts University School of Medicine, discovered how a bacterial protein commandeers host cell activities for its own purposes: to both hide and multiply.

Legionnaires' disease is a type of pneumonia caused by the bacteria Legionella pneumophila. The disease and the bacteria were named after an outbreak of pneumonia at an American Legion convention in Philadelphia in 1976, where the pathogen was first identified.

In healthy human cells, the regulatory protein Rab1 controls the movement of vesicles—cellular cargo containers composed of membrane—between different cell compartments. Other cellular proteins cuddle up to Rab1 to keep it inactive when no cargo needs to be “shipped.” Activating Rab1 requires one cellular protein to grab it and another to activate it. During infection, Legionella's SidM (DrrA) catalyzes both steps in one fell swoop.

Finding a protein that can both grab and activate host protein is rare, says Isberg—and handy. Once Legionella establishes an infection within a membrane-bound vacuole of the host cell, the rapidly multiplying pathogen needs to seize more membrane to avoid outgrowing its confines, much as an expanding family adds on to a house. By hijacking Rab1, Legionella not only acquires the means to add on but also gains control of a critical conductor of vesicle traffic. Thus, the organism can avoid destruction caused by the merger of its cellular home with a vesicle whose job is to degrade invading microbes.

While ingenious, SidM (DrrA) appears to be only one chapter in the story of how Legionella thrives—even if you knock out SidM, the bacteria continue to grow.

“This is like a Russian matryoshka doll story,” says Isberg of the pathogen's layers of defenses. “This organism has many backup systems for recruiting membrane. And 10 percent of its genome encodes proteins that manipulate the [host] cell.”

Photo: Matthias Machner / Isberg Lab