Syphilis Eludes Immune Attack by Shuffling DNA in a Single Gene

By mixing DNA inside and outside of genes, syphilis is one step ahead of the immune system to resist eradication.

Research by UW Medicine in Seattle suggests that Treponema pallidum, the bacterium that causes syphilis, may use a single gene to evade the immune system.

This discovery may help explain how syphilis is latent in the body for decades, thereby frustrating the immune system’s efforts to eradicate syphilis. It can also explain the ability of bacteria to reinfect people who were previously infected and who should have gained some immunity.

Although syphilis can be easily treated with penicillin, the infection rate in the United States has been steadily increasing over the past two decades. In 2018, there were more than 115,000 new infections in the United States.

Worldwide, there are an estimated 6 million new adult cases of syphilis. This infection kills approximately 300,000 fetuses and newborns each year.

However, despite its importance as a cause of disease, little is known about the biology of Treponema pallidum.

One of the reasons for this is that until recently it was impossible to grow it in a laboratory petri dish. Therefore, many laboratory tools used to study other bacteria were not specifically developed for syphilis.

In this study, the researchers compared the genomes of syphilis bacteria collected from a man who had been infected four times. He was recruited by Dr. Christina Marra, professor of neurology, to participate in UW Medicine’s study of cerebrospinal fluid abnormalities in patients with syphilis.

These samples were taken from your blood during two infections six years apart. Among these infections, he was infected and received two treatments.

The researchers wanted to see if there were differences between the bacterial genomes of the first and last infections. These differences can reveal how the bacteria’s genes have changed, and how these changes enable the bacteria to infect a person whose immune system has been observed and who has developed an immune response to several different syphilis strains.

Surprisingly, the researchers found that, except for one gene, there was almost no change between the genomes of two different samples.

“Of the approximately 1.1 million bases that make up the bacterial genome, there are a total of approximately 20 changes. This is very low,” said Dr. Alex Greninger, assistant professor of laboratory medicine at the University of Washington School of Medicine, who led the research project. “But in this gene, we have seen hundreds of changes.”

This gene is called the Treponema pallidum repeat K (tprK) gene and provides instructions for the synthesis of proteins found on the surface of bacteria. Proteins on the surface of bacteria are usually easier to see by immune cells, so they are usually the main targets of immune attacks.

The research is based on decades of work by Drs. Sheila Lukehart and Arturo Centurion-Lara of the Department of Medicine, University of Washington School of Medicine.

They first showed that TprK produces considerable diversity in seven discrete regions, where DNA sequences from other parts of the bacterial genome can be exchanged in and out. This process is called gene conversion.

His laboratory’s work has shown that bacterial cells with new variants of tprK can evade the immune response, leading to persistent infections, leading to late syphilis.

Amin Addetia, a research scientist in Greninger’s laboratory and the lead author of the study, said that it is as if this bacteria has a card in its genome from which it can extract and process these variable regions, fundamentally changing the bacteria’s “hand” . protein. “These substitutions change the appearance of the protein on the surface, allowing it to bypass the immune system.

“I analyzed many bacterial genomes,” Addetia said. “They are much more interesting than Treponema, except for this gene. It can produce an astonishing number of different sequences in these variable regions without affecting the function of the protein.”.

Although the surfaces of bacteria, viruses, and parasites may contain many proteins that the immune system can detect and attack, in many cases, only one protein seems to attract most of the attention. These proteins are called immunodominance.

Greninger says they can protect bacteria by attracting the attention of the immune system. “This protein acts as a dispersal and keeps the immune system away from proteins that may be the Achilles heel of bacteria. More work needs to be done to determine whether TprK is in this case.”

Greninger said that he hopes these findings can help researchers develop vaccines that will allow the immune system to attack TprK more effectively or bypass TprK and target other less mutated syphilis proteins.

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