The bacterium that causes syphilis, Treponema
pallidum, likely uses a single gene to escape the immune system,
research from UW Medicine in Seattle suggests.
The finding may
help explain how syphilis can hide in the body for decades, thereby frustrating
the immune system’s attempts to eradicate it. It might also account for the
bacterium’s ability to re-infect people who had been previously been infected
and 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 count rose to
more than 115,000 new U.S. cases of the infection 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, relatively little
is known about the biology of Treponema pallidum.
One reason for
this is that until recently it was impossible to grow it in a laboratory dish.
As a consequence, many of the laboratory tools used to study other bacteria had
not been developed for syphilis specifically.
In a new study,
researchers compared the genomes of syphilis bacteria collected from a man who
had been infected four times. He was enrolled in a UW Medicine study of spinal
fluid abnormalities in individuals with syphilis conducted by Dr. Christina
Marra, professor of neurolgy.
The samples were
derived from his blood during two infections that occurred six years apart.
Between those infections he had been 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. This differences 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 that there were 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,” said Dr. Alex Greninger, assistant
professor of laboratory medicine at the UW School of Medicine, 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. Proteins on the surface of a bacterium are
typically more easily seen by immune cells and so are often prime targets for
immune attack.
The study builds
on decades of work from Drs. Sheila Lukehart and Arturo Centurion-Lara in the
Department of Medicine at the University of Washington School of Medicine.
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 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 on the study, said 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 said, “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 are called immunodominant.
They may protect
the bacterium by catching the immune system’s attention, Greninger said. “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 said
he hoped 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.
Source: https://myfusimotors.com/2020/04/28/syphilis-eludes-immune-attack-by-altering-a-single-gene/
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