‘Atomic zoom’ brings gum disease bacteria into sharp focus

By Jon Atherton

The technology at the center of the growing ‘resolution revolution’ has again showed its value to scientists at Yale by revealing the secrets of gum disease.

Leveraging the advanced imaging techniques of electron microscopy – or cryo-EM – the lab of Jun Liu, professor of Microbial Pathogenesis at the Yale Microbial Sciences Institute (MSI), has visualized the precise shape and structure of the bacterium Treponema denticola.

One of three bacteria of the so-called Red Complex, Treponema is among the major pathogens that cause chronic periodontal (gum) disease, estimated by the Centers for Disease Control to affect around 40% of U.S. adults over 30.

As their name suggests, spirochetes are long, thin, corkscrew-shaped bacteria well known for their highly invasive nature and ability to move through viscous tissues and spread. 

“We know their movement is driven by tiny hairs, called flagella,” explained Jiaqi Wang, a postdoctoral associate in the Liu Lab at Yale’s West Campus. “We observe them wrapped around the cell body in a sort of supercoil, but no one has been able to explain how the flagella assemble and drive the bacteria.”

Alongside the near-atomic resolution of cryo-EM, Liu has developed a novel ‘team science’ approach to crack a genetic puzzle that has mystified scientists for 50 years. 

A former immunologist by training but attracted to the MSI’s focus on bacteria, Wang brings new expertise in structural biology. The same curiosity to solve the Treponema puzzle motivated her co-first author, associate research scientist Wangbiao Guo, to shift from engineering to the field of microscopy. Chuck Sindelar, a cryo-EM expert at the Yale Center for Research Computing, brought critical insights into the asymmetric nature of spirochetal flagella. 

Building a new protein sequence of the bacterium’s flagellar filament, the scholars were surprised to uncover a two-part assembly quite different from that in other bacteria. 

The findings, which are published in Nature Communications, show the unusual tandem structure propelling the bacteria to drill through our cell tissue and cause gum disease.

“While the hair-like filaments are the driving force of many bacteria, in Treponema denticola we found an asymmetrical assembly made up of a central core and outer sheath enabling the whole spirochete to twist,” said Guo. 

“Zooming in at the atomic level helps us to see in the clearest way what for a long time looked like a blurry bacteria shape,” said Liu of the recent technological advancements.

“Now we can see not just what the flagella look like, but precisely how they function in bacteria.”

West Campus hosts some of the world’s most powerful 3D fluorescence and optical microscopes, allowing researchers to study subcellular dynamics and cellular architecture in real-time.

The technology has led to recent structural breakthroughs such as unravelling how Legionella bacteria cause disease and creating new defenses against COVID-19.

Blending diverse expertise with the latest technology, the work of the Liu Lab is expected to guide the way towards potential orthodontic treatment methods. 

Kurni Kurniyati and Chris Li at Virginia Commonwealth University contributed complementary expertise in microbiology to demonstrate the essential role of flagellar asymmetry in spirochetal motility.