Decoding Legionnaire’s disease

New research led by EPI-IFAS researcher KC Jeong describes for the first time precisely how the Legionnaire’s disease bacterium evades detection by the immune system.

Photo illustration of Legionnaire's disease bacterium.
Photo illustration of Legionnaire’s disease bacterium.

Surviving within a human host is tricky business for a two micrometer-long bacterium, and trickier still for researchers to decode how pathogenic power houses such as Legionella pneumophila evade detection by our immune system. The causative agent of Legionnaire’s diseaseL. pneumophila creates lung infections which can lead to a severe form of pneumonia. Until recently, scientists didn’t fully understand how the bacteria form a protein secretion system named the Dot/Icm T4SS which lets it slip by unnoticed.

In a new study published today in Nature Microbiology, EPI microbiologist KC Jeong and a team of researchers identify and decode pump-like molecular structures, and their biochemical mechanics, in L. pneumophila, which secrete about 300 effector proteins into host cells, through the Dot/Icm T4SS, that suppress a host’s immune response. Their findings, visualized in the video below, form the basis of knowledge needed to design targeted medical interventions to fight Legionnaire’s disease.

Three dimensional representation of the Dot/Icm complex showing a windowed secretion chamber.
Three dimensional representation of the Dot/Icm complex showing a windowed secretion chamber.

“This lays the groundwork needed to develop new medicines,” says Jeong, who is also an associate professor in the department of animal sciences with UF’s Institute of Food and Agricultural Sciences. Jeong’s research team included scientists from the California Institute of Technology, Washington University School of Medicine in St. Louis and The Scripps Research Institute.

It’s not unusual for bacteria to secrete substances that bypass a host’s immune system, but that doesn’t mean scientists always know precisely how the process works. “We have known that this bacterium makes the Dot/Icm T4SS, which are used to evade detection,” Jeong says. “But previously we did not know how the Dot/Icm T4SS is assembled at the bacterial poles to secrete effector proteins through the pump-like apparatus. That is what is new in this study.”

Using two different high-powered imaging techniques — electron cryotomography (above) and immunofluorescence microscopy (below) — Jeong and his team scrutinized the physical structures of L. pneumophila in nanoscale. Prior research published in PNAS by the team in 2017 established that the special protein-secreting structure is located at the bacteria’s poles and that it anchors between the inner and outer membranes in an area formally called the periplasmic space.

Dot/Icm-dependent polar targeting of the Legionella core transmembrane subcomplex.

The hundreds of effector proteins, and their portal into a host through the specialized pumping structure, are what produces disease in people. By describing the mechanics of how the Dot/Icm T4SS is composed and functions, as well as the order in which 27 specific proteins are targeted to the bacterial poles to assemble the secreting pump, Jeong and his team have unlocked a path for biomedical and pharmaceutical researchers to follow.

“Knowing the assembly sequence is key to developing medical interventions to aid infected patients,” Jeong says. “Because if we know the sequence in which the proteins are assembled, we can design something to disrupt them.”

By: DeLene Beeland