The bacterium that causes syphilis likely uses a single gene to escape the immune system, according to new research.

The finding may explain how syphilis can hide in the body for decades, frustrating the immune system’s attempts to eradicate it. It might also account for the bacterium’s ability to re-infect previously infected people who should have acquired some immunity to it.

Although syphilis remains easily treated with penicillin, infection rates in the United States have increased steadily over the past two decades. The infection count rose to more than 115,000 new US cases in 2018.

Worldwide there are an estimated 6 million new cases of syphilis among adults. The infection is responsible for an estimated 300,000 fetal and neonatal deaths annually.

However, despite its importance as a cause of disease, researchers know relatively little about the biology of Treponema pallidum.

One reason for this is that until recently it was not possible to grow it in a laboratory dish. As a consquence, many of the laboratory tools used to study other bacteria had not been developed for syphilis specifically.

1 GENE, HUNDREDS OF CHANGES
For the new study in PLOS Neglected Tropical Diseases researchers compared the genomes of syphilis bacteria collected from a man who had been infected four times. He was enrolled in a University of Washington study of spinal fluid abnormalities in individuals with syphilis.

The researchers derived samples from his blood during two infections that occurred six years apart. Between those infections he was infected and treated two additional times.

The researchers wanted to see if there were differences between the genomes of bacteria from the first and last infection that might reveal how the genes of the bacteria had changed and how those changes might have enabled the bacteria to infect a person whose immune system had already seen and mounted an immune response to several different strains of syphilis.

Surprisingly, the researchers found very few changes between the genomes from the two different samples—except for one gene.

“Across the about 1.1 million bases that make up the bacteria’s genome there were about 20 changes total. That’s very low,” says Alex Greninger, assistant professor of laboratory medicine at the University of Washington who led the research project. “But on this one gene, we saw hundreds of changes.”

That gene, called Treponema pallidum repeat gene K (tprK), provides the instructions for the synthesis of a protein found on the surface of the bacterium. Immune cells more easily see proteins on the surface of a bacterium making so they are often prime targets for immune attack.

SYPHILIS BACTERIUM’S ACHILLES HEEL?
The work builds on decades of work from Sheila Lukehart and Arturo Centurion-Lara. They first showed that TprK generated considerable diversity across seven discrete regions in which DNA sequences from elsewhere in the bacterium’s genome could be swapped in and out.

This process is called gene conversion. Work done in their lab demonstrated that bacterial cells with new tprK variants can evade the immune response to cause a persistent infection that can lead to the later stages of syphilis.

Amin Addetia, a research scientist in Greninger’s lab and lead author of the study, says it was as though the bacterium has a deck of cards in its genome from which it can draw and deal to these variable regions, essentially changing the protein’s “hand.” These substitutions change the protein’s appearance on the surface to allow it to elude the immune system.

“I’ve looked at a lot of bacterial genomes,” Addetia says, “and they’re a lot more interesting than the Treponema’s, except for this one gene. It can generate an astounding number of diverse sequences within these variable regions without impairing the protein’s ability to function.”

Although bacteria, viruses, and parasites may have many proteins on their surfaces that the immune system could detect and attack, in many cases only one protein seems to attract most of the attention.

Such proteins, called immunodominant, may catch the immune system’s attention to protect the bacterium, Greninger says.

“The protein acts like a distraction that draws the immune system away from proteins that might be the bacterium’s Achilles heel. More work will be required to determine if this is the case in TprK.”

Greninger says he hopes the findings might help researchers develop vaccines that allow the immune system either to attack TprK more effectively or to ignore TprK and target other, less variable syphilis proteins.

The National Institutes of Allergy and Infectious Disease supported the work.